Choroba zwyrodnieniowa stawów – Patofizjologia i mechanizm

Choroba zwyrodnieniowa stawów
Patofizjologia i mechanizm

Choroba zwyrodnieniowa stawów (OA) jest schorzeniem wieloczynnikowym obejmującym zmiany w chrząstce stawowej, kości podchrzęstnej, błonie maziowej oraz innych strukturach stawu. Patogeneza OA wiąże się z zaburzeniem równowagi między syntezą a degradacją macierzy zewnątrzkomórkowej chrząstki, gdzie kluczową rolę odgrywają metaloproteinazy macierzy (MMPs), agrekanazy ADAMTS oraz cytokiny prozapalne, takie jak IL-1 i TNF-α. Procesy zapalne o niskim nasileniu, aktywacja szlaków sygnałowych (TGF-β, Wnt/β-katenina, NF-κB) oraz mechanizmy epigenetyczne (metylacja DNA, modyfikacje histonów, mikroRNA) wpływają na progresję choroby. Zmiany w kości podchrzęstnej, takie jak hipomineralizacja, zwiększony obrót kostny i unaczynienie, przyczyniają się do zaburzenia biomechaniki stawu i odczuwania bólu. Czynniki mechaniczne, starzenie się chondrocytów, stres oksydacyjny oraz predyspozycje genetyczne (ponad 80 mutacji i SNP, m.in. Smad3) są istotnymi elementami etiologii OA.

Patogeneza Choroby Zwyrodnieniowej Stawów

Choroba zwyrodnieniowa stawów (OA) jest najczęstszą chorobą zwyrodnieniową stawów i główną przyczyną niepełnosprawności, mającą znaczący wpływ społeczno-ekonomiczny. Jest to schorzenie wieloczynnikowe, które wpływa na cały staw, a nie tylko na chrząstkę stawową, jak wcześniej uważano. W patogenezie OA uczestniczą zmiany w chrząstce stawowej, kości podchrzęstnej, błonie maziowej, łąkotkach, więzadłach, mięśniach okołostawowych i nerwach.¹²

Zaburzenie homeostazy chrząstki stawowej

Choroba zwyrodnieniowa stawów wynika z zaburzenia homeostazy między syntezą a degradacją składników macierzy zewnątrzkomórkowej chrząstki. Chondrocyty, jedyny typ komórek w chrząstce stawowej, są odpowiedzialne za utrzymanie równowagi między procesami anabolicznymi i katabolicznymi. W OA dochodzi do zachwiania tej równowagi, co prowadzi do przewagi procesów degradacyjnych nad naprawczymi.²³

Początkowo w odpowiedzi na uszkodzenie chrząstki aktywują się mechanizmy kompensacyjne, takie jak zwiększona synteza cząsteczek macierzy (kolagenu, proteoglikanów i kwasu hialuronowego) oraz proliferacja chondrocytów w głębszych warstwach chrząstki. Jednak z czasem procesy degradacyjne przeważają nad naprawczymi i rozwijają się zmiany zwyrodnieniowe.³⁴

Molekularne mechanizmy degradacji chrząstki

W patogenezie OA kluczową rolę odgrywają enzymy degradujące macierz, głównie metaloproteinazy macierzy (MMPs) oraz agrekanazy z rodziny ADAMTS. Enzymy te są nadmiernie produkowane w OA, co prowadzi do degradacji kolagenu i proteoglikanów w macierzy chrząstki.⁵⁶

Istotną rolę w stymulacji produkcji enzymów degradujących pełnią cytokiny prozapalne, zwłaszcza interleukina-1 (IL-1) i czynnik martwicy nowotworów alfa (TNF-α). IL-1 nie tylko aktywnie promuje degradację chrząstki, ale również hamuje procesy naprawcze. Dodatkowo, w patogenezie OA uczestniczą szlaki sygnałowe TGF-β, Wnt/β-katenina, Indian Hedgehog (Ihh), Notch i FGF, które przyczyniają się do rozwoju i progresji choroby poprzez indukcję odpowiedzi katabolicznej w chondrocytach.⁵⁷

Czynnikiem transkrypcyjnym, który bezpośrednio reguluje transkrypcję genów kodujących enzymy degradujące macierz w chondrocytach stawowych, jest Runx2. Jego nadekspresja jest wspólną cechą wielu modeli zwierzęcych OA.⁸

Rola stanu zapalnego w patogenezie OA

Choroba zwyrodnieniowa stawów była tradycyjnie uważana za chorobę niezapalną, jednak coraz więcej dowodów wskazuje na istotną rolę przewlekłego stanu zapalnego o niskim nasileniu w jej rozwoju i progresji.⁸⁹

W patogenezie OA biorą udział sygnały zapalne wrodzonej odpowiedzi immunologicznej, w tym wzorce molekularne związane z uszkodzeniem (DAMPs), alarminy (S100A8 i S100A9) oraz układ dopełniacza. Badania wykazały, że stan zapalny ogólnoustrojowy może przeprogramować chondrocyty poprzez mediatory zapalne w kierunku różnicowania hypertroficznego i odpowiedzi katabolicznej poprzez szlak NF-κB, oś ZIP8/Zn²⁺/MTF1 oraz mechanizmy autofagii.⁸¹⁰

Analizy szlaków KEGG (Kyoto Encyclopedia of Genes and Genomes) próbek OA i kontrolnych dostarczają dowodów, że sygnały zapalne przyczyniają się do patogenezy OA poprzez cytokiny indukujące kinazy aktywowane mitogenami (MAP), aktywację NF-κB i fosforylację oksydacyjną.⁷

Zmiany w kości podchrzęstnej

Kość podchrzęstna odgrywa istotną rolę w patogenezie OA. W przebiegu choroby obserwuje się zwiększoną objętość kości podchrzęstnej i jej demineralizację (hipomineralizacja). Dochodzi do przebudowy kości podchrzęstnej, co prowadzi do tworzenia osteofitów i torbieli podchrzęstnych.¹¹¹²

W kości podchrzęstnej w OA występuje zwiększony obrót kostny, ze zwiększoną aktywnością osteoblastów i osteoklastów oraz zmienioną sygnalizacją osteocytów. Zmiany te prowadzą do stwardnienia kości podchrzęstnej, co zaburza zdolność tkanki do amortyzacji obciążeń mechanicznych.¹³¹⁴

Istotnym aspektem jest również zwiększona unaczynienie kości podchrzęstnej w OA. Nowo utworzone naczynia i włókna nerwowe w przebudowanej kości podchrzęstnej prawdopodobnie uczestniczą w patogenezie OA i odczuwaniu bólu.¹⁴¹⁵

Rola czynników mechanicznych

Czynniki biomechaniczne odgrywają kluczową rolę w patogenezie OA, szczególnie w przypadku stawów obciążonych. Zmienione mechanizmy obciążenia, zwiększone siły mechaniczne i zmieniona biomechanika są istotnymi czynnikami przyczyniającymi się do inicjacji i progresji OA.¹⁶

OA rozwija się, gdy dynamiczna równowaga między siłami destrukcyjnymi a mechanizmami naprawczymi zostaje zaburzona, co prowadzi do destabilizacji homeostazy stawu. Zarówno nadmierne obciążenie mechaniczne, jak i odciążenie stawu są kluczowe dla początku i progresji choroby.¹⁴¹⁷

W przypadku kolan i stawów skokowych, objawy OA typowo pojawiają się, gdy pacjenci są w aktywnym wieku średnim, ponieważ uraz jest dominującą przyczyną ich OA. Skuteczność chirurgii realignacyjnej w przywracaniu prawie normalnej biomechaniki wykazała, że jest to potężne narzędzie do przywrócenia równowagi sił biomechanicznych w stawie z następową reakcją kostną.¹⁸

Epigenetyczna regulacja w OA

Regulacja epigenetyczna to nowo wyłaniający się obszar związany ze zmianami w ekspresji genów katabolicznych i anabolicznych w chondrocytach z OA. Badania koncentrują się na metylacji DNA, modyfikacji histonów i regulacji mikroRNA, które zostały powiązane z OA.¹⁹²⁰

Wykazano krytyczną rolę metylotransferaz DNA (DNMTs) w rozwoju OA, co sugeruje, że mogą być one nowymi celami molekularnymi w leczeniu OA. Podobnie, metylacja histonów uczestniczy w patogenezie OA poprzez regulację aktywności anabolicznej i katabolicznej w chondrocytach.²⁰

Znaczące postępy osiągnięto w wyjaśnianiu roli SIRT1 (Sirtuin 1) w patologicznej progresji OA. Badania sugerują, że aktywacja SIRT1 może służyć jako idealna strategia terapeutyczna w leczeniu OA. Ponadto, mikroRNA są ściśle związane z regulacją rozwoju i progresji OA.²⁰²¹

Starzenie się komórek i OA

Zwiększona liczba starzejących się chondrocytów jest obserwowana w chrząstce OA. Środowisko zapalne indukowane przez czynniki SASP (fenotyp sekrecyjny związany ze starzeniem się) jest zaangażowane w degenerację chrząstki i przebudowę kości podchrzęstnej, co ostatecznie prowadzi do utraty chrząstki i progresji OA.²²

Mechanizmy prowadzące do starzenia się są liczne i złożone. Nadmierne obciążenie mechaniczne sprzyja starzeniu się w hodowanych in vitro chondrocytach i w chrząstce myszy. Starzejące się komórki produkują czynniki SASP, które promują środowisko zapalne i katabolizm chrząstki.²³

Stres mechaniczny i starzenie się są dwoma głównymi czynnikami ryzyka OA, które mogą wytwarzać reaktywne formy tlenu (ROS) i stres oksydacyjny. Dysfunkcja mitochondrialna i stres oksydacyjny są kluczowymi czynnikami w OA.²³

Czynniki genetyczne w rozwoju OA

Predyspozycja dziedziczna do OA jest znana od wielu lat z badań rodzinnych. Chociaż genetyka OA jest złożona, wkład genetyczny w OA jest bardzo istotny. Badania przesiewowe asocjacji w całym genomie (GWAS) przeprowadzone na dużej liczbie populacji OA i kontrolnych potwierdziły ponad 80 mutacji genów lub polimorfizmów pojedynczych nukleotydów (SNP) zaangażowanych w patogenezę OA.⁷⁶

W szczególności, mutacje Smad3, centralnej cząsteczki w sygnalizacji TGF-β, zostały znalezione u pacjentów z wczesnym początkiem OA. Odkrycia te sugerują, że sygnalizacja TGF-β może mieć zróżnicowane role w różnych tkankach stawu i że interwencje terapeutyczne ukierunkowane na sygnalizację TGF-β mogą wymagać podejścia specyficznego dla tkanki.⁶

Niedawne badanie z Uniwersytetu w Sheffield zidentyfikowało ponad 900 powiązań genetycznych z osteoartrozą, w tym 500, które nigdy wcześniej nie były zgłaszane. Odkryto również osiem procesów biologicznych zaangażowanych w regulację wewnętrznych systemów organizmu i funkcji komórek, rzucając światło na biologiczny mechanizm choroby, w tym zarówno zegar okołodobowy, jak i ścieżki sygnalizacji rozwojowej.²⁴

Nowoczesne podejście do patogenezy OA

Nowe mechanizmy śmierci komórek w OA

Ostatnie badania dostarczyły nowych informacji na temat roli nowych form regulowanej śmierci komórek w patogenezie OA, w tym pyroptozy, ferrptozy i autofagii. Każdy z tych procesów odgrywa indywidualną rolę w OA i stanowi potencjalny cel molekularny w leczeniu choroby.¹⁹²⁵

Autofagia jest mechanizmem ochronnym w normalnej chrząstce, a jej utrata związana ze starzeniem się jest powiązana ze śmiercią komórek i rozwojem OA. Z kolei, ferroptoza chondrocytów przyczynia się do progresji OA, a nadmierne obciążenie mechaniczne indukuje regulowaną przez GPX4 ferroptezę chondrocytów w OA za pośrednictwem kanału Piezo1 ułatwiającego napływ wapnia.²⁵

Mechanorecepcja i zapalenie

Interleukina-17 (IL-17) jest cytokiną, która promuje aktywację wielu szlaków katabolicznych, prowadzących do uszkodzenia chrząstki i tkanki. Zwiększony poziom IL-17 w surowicy pacjentów z wczesnym OA kolana sugeruje jej patogenną rolę w chorobie.²⁶

Badania wykazały, że IL-17A odgrywa rolę w patofizjologii OA, a chondrocyty od pacjentów z OA leczone IL-17 wykazywały zwiększoną ekspresję czynników katabolicznych, które są zaangażowane w niszczenie chrząstki w OA. Poziom IL-17 w surowicy korelował również z funkcjonalnym wynikiem KOOS i był dodatnio skorelowany z oceną podskali bólu KOOS.²⁶²⁷

Płeć a rozwój OA

Badania wykazały związek między menopauzą a zwiększonym ryzykiem OA. Zmiany hormonalne związane z menopauzą przyspieszają rozwój i progresję OA, jednak dokładne mechanizmy biologiczne leżące u podstaw tej korelacji nie były w pełni zrozumiane.²⁸

Odkryto, że wywołana menopauzą utrata estrogenu i progesteronu promuje degradację macierzy zewnątrzkomórkowej i pogorszenie stanu chondrocytów, podczas gdy przywrócenie tych hormonów do poziomów przedmenopauzalnych chroniło przed degeneracją chrząstki. Badania te dostarczają wyjaśnienia, dlaczego obserwowane od dawna różnice płciowe w częstości występowania osteoartrozy mogą występować.²⁹

Rola układu limfatycznego błony maziowej

Układ limfatyczny błony maziowej odgrywa ważną rolę w usuwaniu czynników katabolicznych pochodzących z chrząstki w błonie maziowej stawów z OA, co otwiera nowe kierunki badań. Mimo znaczących postępów w zrozumieniu patogenezy OA, etiologia i mechanizmy patologiczne OA nie są jeszcze w pełni poznane.²¹

Rola fibrynolitycznych szlaków w OA

Coraz więcej dowodów sugeruje, że aktywacja fibrynolizy jest zaangażowana w patogenezę OA. Wykazano, że szlak fibrynolityczny, który obejmuje plazminogen/plazminę, tkankowy aktywator plazminogenu, urokinazowy aktywator plazminogenu (uPA) i receptor uPA (uPAR), jest zaburzony w ludzkich stawach z OA.³⁰

Farmakologiczne hamowanie plazminy łagodziło progresję OA po destabilizacji przyśrodkowej łąkotki w modelu mysim, podczas gdy genetyczny niedobór inhibitora aktywatora plazminy lub wstrzyknięcie plazminy zaostrzały OA. Badania in vitro wykazały, że plazmina promuje rozwój OA poprzez wiele mechanizmów, w tym degradację lubrycyny i proteoglikanów chrząstki oraz indukcję mediatorów zapalnych i degradacyjnych.³⁰³¹

Implikacje kliniczne i terapeutyczne

Diagnostyka i wczesna interwencja

Dokładne molekularne mechanizmy OA są obecnie nieznane, co utrudnia opracowanie skutecznych metod diagnostycznych i leczniczych. Nie ma zatwierdzonych skutecznych leków modyfikujących przebieg choroby zwyrodnieniowej stawów (DMOADs), co częściowo wynika z braku pełnego zrozumienia patogenezy OA.²³²

Wczesna diagnoza, terminowa identyfikacja i interwencja w przypadku OA kolana mają potencjał spowolnienia, zatrzymania, a nawet odwrócenia choroby, znacznie poprawiając rokowanie pacjenta i jakość życia. Obecnie diagnostyka osteoartrozy opiera się głównie na historii medycznej pacjenta, objawach klinicznych i obrazowaniu medycznym.³³

Powszechnie akceptowanymi kryteriami diagnostycznymi dla OA kolana są system stopniowania Kellgrena-Lawrence’a (KL) i atlas dostarczony przez Międzynarodowe Towarzystwo Badań nad Osteoartrozą (OARSI). W ostatnich latach szybki rozwój sztucznej inteligencji znalazł szerokie zastosowanie w inteligentnym rozpoznawaniu i pomocniczej diagnostyce osteoartrozy.³³

Nowe cele terapeutyczne

Lepsze zrozumienie patogenezy OA jest niezbędne do opracowania bardziej specyficznych i skutecznych interwencji terapeutycznych. Badania koncentrują się na opracowaniu leków modyfikujących przebieg choroby, które mogą spowolnić lub zatrzymać postęp OA.²⁵³⁴

Wśród potencjalnych celów terapeutycznych wymienia się receptory aktywatora czynnika jądrowego kappa-B ligand (RANK-L), który jest zaangażowany w proces erozji zapalnych chorób stawów i może odgrywać rolę w erozyjnym procesie OA.³⁵

Innym obiecującym celem jest receptor związany z estrogenem gamma (ERRγ), który działa jako kataboliczny regulator patogenezy OA. Badania wykazały, że ERRγ jest znacząco zwiększony w ludzkiej i mysiej chrząstce OA, a jego wyciszenie genetyczne lub ablacja hamuje patogenezę OA spowodowaną operacją DMM. Wyniki te wskazują, że ERRγ działa jako kataboliczny regulator degeneracji chrząstki i patogenezy OA i może być celem terapeutycznym dla OA.³⁶³⁷

Niedawno odkryto również nowy mechanizm, który łączy sztywnienie tkanki chrzęstnej związane z wiekiem z represją kluczowego białka związanego z długowiecznością – Klotho. Analiza ujawniła, że gdy tkanka chrzęstna stawu kolanowego stawała się sztywniejsza, gen kodujący Klotho był represjonowany. Wyniki te dostarczają przekonującego nowego paradygmatu, który będzie ważny dla zrozumienia związku między sztywnieniem tkanki związanym z wiekiem a ryzykiem osteoartrozy w związku ze starzeniem się.³⁸³⁹

Modele eksperymentalne i nowe technologie

Brak biologicznie istotnych modeli do odtworzenia patogenezy ludzkiej OA stanowi jedną z głównych przeszkód w rozwoju DMOADs. Badania zajmują się obecnymi modelami eksperymentalnymi OA in vivo i in vitro, ze szczególnym naciskiem na niedawny rozwój i potencjał zastosowania ludzkich platform mikrofizjologicznych chipów tkankowych pochodzących z komórek.⁴⁰

W jednym z badań opracowano system jednostki kostno-chrzęstnej (OCU) na chipie, w którym kompozytowe mikrotkanki analogiczne do chrząstki hialinowej i zmineralizowanej tkanki kostnej są poddawane kontrolowanym, specyficznym dla tkanki reżimom kompresji, podobnym do tych, które występują in vivo. Poprzez analizę transkryptomiczną pojedynczych komórek wykazano krytyczne znaczenie warstwy zmineralizowanej w indukowaniu subpopulacji chondrocytów zaangażowanych w progresję OA.⁴¹

System ten umożliwił identyfikację nowych czynników inicjujących zmiany metaboliczne w OA, w tym mechanicznie indukowanych zmian rybosomalnych, a także powiązanych celów molekularnych do opracowania terapii modyfikujących przebieg OA.⁴¹

Nowe technologie, takie jak CRISPR, sekwencjonowanie RNA pojedynczych komórek i śledzenie linii komórkowej, są i będą nadal wykorzystywane w dziedzinie OA i bólu związanego z OA, co pozwala na lepsze zrozumienie mechanizmów patologicznych OA.⁴²

Medycyna precyzyjna w OA

OA jest chorobą heterogenną, a zmiany patologiczne, a co za tym idzie objawy, różnią się u poszczególnych osób, podkreślając krytyczną potrzebę spersonalizowanych terapii. Większość przypadków OA ma jasne predysponujące warunki, takie jak genetyka, uraz, starzenie się lub otyłość, co prowadzi do idei, że OA opisuje wspólny punkt końcowy o różnych etiologiach.⁴³⁴⁴

Istnieje znaczna heterogenność wśród pacjentów z osteoartrozą i coraz więcej dowodów, że szlaki zaangażowane w OA (np. sygnalizacja Wnt) różnią się między podgrupami pacjentów. Stwierdzono również, że szlaki zaangażowane w OA różnią się między myszim modelem STR/ort (najbardziej intensywnie badanym myszim modelem spontanicznie występującej OA) a modelami OA indukowanymi urazem.⁴⁵

Na przykład, podczas gdy kanoniczny szlak sygnalizacyjny Wnt jest zwiększony w błonie maziowej i chrząstce we wczesnym stadium choroby w modelach OA indukowanych urazem, nie wydaje się to być przypadkiem u myszy STR/ort. Takie odkrycia mogą okazać się pomocne dla zrozumienia heterogenności mechanizmów zaangażowanych w patogenezę OA w chorobie ludzkiej.⁴⁵

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Materiały źródłowe

#1
https://pmc.ncbi.nlm.nih.gov/articles/PMC3956093/
Osteoarthritis is the most common joint disorder and a major cause of disability with a major socio-economic impact. In these circumstances is very important to understand its pathogenesis. Although previous research focused primarily on changes in the articular cartilage, more recent studies have highlighted the importance of the subchondral bone, synovium, menisci, ligaments, periarticular muscles and nerves. Now osteoarthritis is viewed as a multifactorial disease affecting the whole joint. […] Initially, osteoarthritis has been considered to be a disease of articular cartilage, but recent research has indicated that the condition involves the entire joint. The loss of articular cartilage has been thought to be the primary change, but a combination of cellular changes and biomechanical stresses causes several secondary changes, including subchondral bone remodeling, the formation of osteophytes, the development of bone marrow lesions, change in the synovium, joint capsule, ligaments and periarticular muscles, and meniscal tears and extrusion.
#2 Pathogenesis of Osteoarthritis: Risk Factors, Regulatory Pathways in Chondrocytes, and Experimental Models
https://pmc.ncbi.nlm.nih.gov/articles/PMC7464998/
As the most common chronic degenerative joint disease, osteoarthritis (OA) is the leading cause of pain and physical disability, affecting millions of people worldwide. […] Pathological changes, and thus symptoms, vary from person to person, underscoring the critical need of personalized therapies. […] However, there has only been limited progress towards the prevention and treatment of OA, and there are no approved effective disease-modifying osteoarthritis drugs (DMOADs). […] In this review, we provide an update of the known OA risk factors and relevant mechanisms of action. […] OA is characterized as a failure of the joint organ that affects all the tissues in and around the joint, these affects include degradation of the articular cartilage; thickening of the subchondral bone; osteophyte formation; variable degrees of synovial inflammation; degeneration of ligaments; hypertrophy of the joint capsule; and changes in periarticular muscles, nerves, bursa, and local fat pads.
#2
https://pmc.ncbi.nlm.nih.gov/articles/PMC3956093/
Osteoarthritis result from failure of chondrocytes to maintain homeostasis between synthesis and degradation of these extracellular matrix components. It is not known what initiates the imbalance between the degradation and the repair of cartilage. Trauma causing a microfracture or inflammation causing a slight increase in enzymatic activity may allow the formation of wear particles, which could be then engulfed by resident macrophages. At some point in time, the production of these wear particles overwhelms the ability of the system to eliminate them and they become mediators of inflammation, stimulating the chondrocyte to release degradative enzymes. […] This disruption of homeostasis results in increased water content and decreased proteoglycan content of the extracellular matrix, weakening of the collagen network due to decreased synthesis of type II collagen and increased breakdown of pre-existing collagen. Furthermore, there is increased apoptosis of chondrocytes.
#3 Pathogenesis of Osteoarthritis: Risk Factors, Regulatory Pathways in Chondrocytes, and Experimental Models
https://pmc.ncbi.nlm.nih.gov/articles/PMC7464998/
Among these, cartilage degradation is considered to be the central feature. […] In OA, dysregulation caused by the presence of various biofactors leads to the loss of cartilage homeostasis, resulting in degradation of the collagen- and proteoglycan-rich extracellular matrix (ECM), fibrillation and erosion of the articular surface, cell death, matrix calcification, and vascular invasion. […] Despite the disease being known for centuries, the exact pathogenic mechanisms of OA remain unclear. […] However, detailed examination revealed patient-specific variability in the clinical presentation and disease progression. […] Most cases of OA have a clear predisposing condition, such as genetics, trauma, aging, or obesity, leading to the idea that OA describes a common endpoint with different etiologies.
#3
https://pmc.ncbi.nlm.nih.gov/articles/PMC3956093/
Osteoarthritic cartilage is characterized by an increase in anabolic and catabolic activity. At first, compensatory mechanisms such as increased synthesis of matrix molecules (collagen, proteoglycans and hyaluronate) and proliferation of chondrocytes in the deeper layers of the cartilage, are able to maintain the integrity of the articular cartilage, but in the end loss of chondrocytes and changes in extracellular matrix predominate and osteoarthritic changes develop. […] In conclusion, osteoarthritis is a multifactorial disease of whole joint, with a complex pathomechanism involving interaction between the multiple joint tissue. Knowing of this complex process of producing osteoarthritis is essential for development of new methods of diagnostic and treatment.
#4 Osteoarthritis: Practice Essentials, Background, Anatomy
https://emedicine.medscape.com/article/330487-overview
Traditionally, osteoarthritis was thought to affect primarily the articular cartilage of synovial joints; however, pathophysiologic changes are also known to occur in the synovial fluid, as well as in the underlying (subchondral) bone, the overlying joint capsule, and other joint tissues. […] Although osteoarthritis has been classified as a noninflammatory arthritis, increasing evidence has shown that inflammation occurs as cytokines and metalloproteinases are released into the joint. These agents are involved in the excessive matrix degradation that characterizes cartilage degeneration in osteoarthritis. Therefore, it is no longer appropriate to use the term degenerative joint disease when referring to osteoarthritis. […] In early osteoarthritis, swelling of the cartilage usually occurs, because of the increased synthesis of proteoglycans; this reflects an effort by the chondrocytes to repair cartilage damage. However, proinflammatory cytokines result in deterioration of chondrocyte metabolism. This stage may last for years or decades and is characterized by hypertrophic repair of the articular cartilage.
#5 Osteoarthritis : Pathophysiology
https://www.hopkinsarthritis.org/arthritis-info/osteoarthritis/oa-pathophysiology/
OA is primarily a disease of cartilage […] In OA cartilage, however, matrix degrading enzymes are overexpressed, shifting this balance in favor of net degradation, with resultant loss of collagen and proteoglycans from the matrix. […] A critical question is whether OA is truly a disease or a natural consequence of aging. […] The primary enzymes responsible for the degradation of cartilage are the matrix metalloproteinases (MMPs). […] In OA, synthesis of MMPs is greatly enhanced and the available inhibitors are overwhelmed, resulting in net degradation. […] One candidate is interleukin-1 (IL-1). […] Thus, IL-1 may not only actively promote cartilage degradation, but may also suppress attempts at repair, in OA. […] Growth factors are produced locally in cartilage and synovium and are likely to contribute to local cartilage remodeling by stimulating the de novo synthesis of collagen and proteoglycans. […] In summary, MMPs and pro-inflammatory cytokines (e.g., IL-1) appear to be important mediators of cartilage destruction in OA.
#6 Osteoarthritis: toward a comprehensive understanding of pathological mechanism | Bone Research
https://www.nature.com/articles/boneres201644
Such responses converge on Hif2, Runx2, and inflammatory mediators that lead to cartilage ECM degradation through the increased expression of MMPs and ADAMTS activity. […] Recent studies of genome-wide association screens (GWAS) that have been performed on large numbers of OA and control populations throughout the world have confirmed over 80 gene mutations or single-nucleotide polymorphisms (SNPs) involved in OA pathogenesis. […] TGF- and its downstream molecules have important roles in OA pathogenesis. […] Mutations of Smad3, a central molecule in TGF- signaling, have been found in patients with early-onset OA. […] It has been known for years that TGF- promotes mesenchymal progenitor cell differentiation and matrix protein synthesis and inhibits chondrocyte hypertrophy. […] These findings suggest that TGF- signaling may have differential roles in various joint tissues and that therapeutic interventions targeting TGF- signaling may require a tissue-specific approach.
#7 Osteoarthritis: toward a comprehensive understanding of pathological mechanism | Bone Research
https://www.nature.com/articles/boneres201644
Indeed, the recent Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of OA and control samples provide evidence that inflammation signals contribute to OA pathogenesis through cytokine-induced mitogen-activated protein (MAP) kinases, NF-B activation, and oxidative phosphorylation. […] An inherited predisposition to OA has been known for many years from family-based studies. […] Although the genetics of OA are complex, the genetic contribution to OA is highly significant. […] Over the past decade, the roles of genes and signaling pathways in OA pathogenesis have been demonstrated by ex vivo studies using tissues derived from OA patients and in vivo studies using surgically induced OA animal models and genetic mouse models. […] For example, alterations in TGF-, Wnt/-catenin, Indian Hedgehog (Ihh), Notch and fibroblast growth factor (FGF) pathways have been shown to contribute to OA development and progression by primarily inducing catabolic responses in chondrocytes.
#8 Osteoarthritis: toward a comprehensive understanding of pathological mechanism | Bone Research
https://www.nature.com/articles/boneres201644
One feature common to several OA animal models is the upregulation of Runx2. […] Runx2 is a key transcription factor directly regulating the transcription of genes encoding matrix degradation enzymes in articular chondrocytes. […] It has been established that the chronic low-grade inflammation found in OA contributes to disease development and progression. […] During OA progression, the entire synovial joint, including cartilage, subchondral bone, and synovium, are involved in the inflammation process. […] Innate inflammatory signals were also involved in OA pathogenesis, including damage associated molecular patterns (DAMPs), alarmins (S100A8 and S100A9) and complement. […] Recent studies further clarified that systemic inflammation can re-program chondrocytes through inflammatory mediators toward hypertrophic differentiation and catabolic responses through the NF-B pathway, the ZIP8/Zn+/MTF1 axis, and autophagy mechanisms.
#9 Osteoarthritis: Practice Essentials, Background, Anatomy
https://emedicine.medscape.com/article/330487-overview
Osteoarthritis is the most common type of joint disease, affecting more than 30 million individuals in the United States alone. It can be thought of as primarily a degenerative disorder with inflammatory components arising from the biochemical breakdown of articular (hyaline) cartilage in the synovial joints. The current view holds that osteoarthritis involves not only the articular cartilage but the entire joint organ, including the subchondral bone and synovium. […] Although osteoarthritis was previously thought to be caused largely by excessive wear and tear, increasing evidence points to the contributions of abnormal mechanics and inflammation. In addition, some invasive procedures (eg, arthroscopic meniscectomy) can result in rapid progression to osteoarthritis in the knee joint. Therefore, the term degenerative joint disease is no longer appropriate in referring to osteoarthritis.
#10 The Immunological Facets of Chondrocytes in Osteoarthritis: A Narrative Review | The Journal of Rheumatology
https://www.jrheum.org/content/51/1/13
Osteoarthritis (OA) is a disease in which the pathogenesis affects the joint and its surrounding tissues. Cartilage degeneration is the main hallmark of OA, and chondrocytes within the cartilage regulate matrix production and degradation. In patients with OA and in animal models of OA, the pathology of the disease relates to disequilibrium between anabolic and catabolic states of the cartilage. Moreover, chondrocyte phenotype and function are also immunologically altered. Under inflammatory conditions, chondrocytes increase production levels of inflammatory cytokines and cartilage-degrading enzymes, which further drive cartilage destruction. Chondrocytes also have an innate immune function and respond to damage-associated molecular patterns (DAMPs) and cartilage fragments by innate immune receptors. In addition, chondrocytes play a role in adaptive immune responses by acting as antigen-presenting cells and presenting cartilaginous antigens to T cells. Indirectly, chondrocytes are stimulated by pathogen-associated molecular patterns (PAMPs) present in the joints, a result of the microbiota of the host. Chondrocytes have both direct and indirect relationships with immune cells and the immune compartment of patients with OA. Therefore, chondrocytes serve as a target for immunotherapeutic approaches in OA.
#11 Osteoarthritis – Wikipedia
https://en.wikipedia.org/wiki/Osteoarthritis
The breakdown of collagen fibers results in a net increase in water content. […] Other structures within the joint can also be affected. […] The ligaments within the joint become thickened and fibrotic, and the menisci can become damaged and wear away. […] The subchondral bone volume increases and becomes less mineralized (hypo mineralization). […] All these changes can cause problems functioning.
#12 Osteoarthritis – Pathophysiology – Clinical Features – TeachMeSurgery
https://teachmesurgery.com/orthopaedic/principles/osteoarthritis/
Osteoarthritis is traditionally thought of as a wear and tear disease which occurs as we age. However, recent research suggests otherwise. […] The pathogenesis of OA involves a degradation of cartilage and remodelling of bone due to an active response of chondrocytes in the articular cartilage and the inflammatory cells in the surrounding tissues. […] The release of enzymes from these cells break down collagen and proteoglycans, destroying the articular cartilage. The exposure of the underlying subchondral bone results in sclerosis, followed by reactive remodelling changes that lead to the formation of osteophytes and subchondral bone cysts. The joint space is progressively lost over time. […] Osteoarthritis is a condition characterised by the progressive loss of articular cartilage and remodelling of the underlying bone.
#13 Re-thinking osteoarthritis pathogenesis: what can we learn (and what do we need to unlearn) from mouse models about the mechanisms involved in disease development | Arthritis Research & Therapy | Full Text
https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-023-03042-6
In humans, OA is associated with pathological changes in multiple joint tissues including the cartilage, subchondral bone, synovium, ligaments, and meniscus as well as a change in the composition of the fat pad. These changes lead to structural joint remodelling resulting in impaired joint mobility and pain. […] Both the amount and the composition of articular cartilage change in OA. During early OA, the water content of cartilage increases in conjunction with changes in proteoglycan content, and the resultant cartilage swelling can result in a temporary increase in cartilage thickness. Continual proteoglycan loss and type II collagen degradation lead to net cartilage attrition, and this is a major cause of joint space narrowing in disease. […] In OA, synovitis is associated with fibrosis, increased vascularity, hyperplasia, and inflammation. There is an increase in the proliferation of the resident fibroblast-like synoviocytes (FLS), and immune cell infiltration can occur with macrophage, T cell, and mast cell enrichment evident. […] Changes in both the cortical subchondral bone plate and underlying trabecular bone are evident in patients with OA. In humans, subchondral bone turnover is increased, with increased formation and activity of osteoblasts and osteoclasts and altered osteocyte signalling.
#14 Biomechanics and pathomechanisms ofÂ osteoarthritis
https://smw.ch/index.php/smw/article/download/1523/1931
OA is regarded as a whole joint disease with a multifactorial etiology, including increased mechanical stress, ligament derangements, cartilage degradation, subchondral bone changes and muscular impairments. […] Several studies pointed out the importance of mechanical factors in the destructive cascade of this disease. […] OA occurs when the dynamic steady state between destructive forces and repair mechanisms destabilises the joint homeostasis. […] This imbalance is thought to be the driving force in this progressive disease and may produce pain and disability. […] The role of bone density in OA is currently debated. […] However, at a later stage, subchondral bone sclerosis and higher bone density are seen radiologically. […] The newly organised subchondral bone also contains new vessels and nerve fibers, which are likely involved in OA pathogenesis and pain sensation, respectively.
#15 Single-cell RNA-sequencing analysis reveals the molecular mechanism of subchondral bone cell heterogeneity in the development of osteoarthritis | RMD Open
https://rmdopen.bmj.com/content/8/2/e002314
The first stage of OB differentiation is characterised by cell proliferation. […] In the process of OA cartilage erosion, compared with the top-down vessel invasion originating from synovial tissue or synovium, bottom-up vascularisation from subchondral bone plays a larger role. […] The characterisation of these two novel subsets improves our understanding of the characteristics and functions of ECs in the OA subchondral bone.
#16 Biomechanics and pathomechanisms ofÂ osteoarthritis
https://smw.ch/index.php/smw/article/download/1523/1931
Today, the most frequent chronic musculoskeletal disorder and the leading cause of disability in the elderly is osteoarthritis (OA). […] Despite the exact cause of OA remains unknown, the pathogenic role of biomechanical dysfunction in OA is well established. […] For weight-bearing joints altered loading mechanisms, increased mechanical forces and changed biomechanics are significant contributing factors for initiation and progression of OA. […] The role of biomechanics in the development and progression of OA, especially of the lower limb has become integral in current knowledge of this disease. […] In this review we focus on the influence of different biomechanical factors on the pathogenesis and progression of OA, underlining the pathological bioreactivity of soft tissues, subchondral bone and subsequent joint inflammation.
#17 Biomechanics and pathomechanisms ofÂ osteoarthritis
https://smw.ch/index.php/smw/article/download/1523/1931
A joint represents the connective unit between two bones or functional segments. […] Adequate mechanical loading provides the essential stimulus to maintain physiological joint homeostasis, whereas excessive mechanical stress as well as unloading the joint is crucial for the disease onset and progression. […] Over the last two decades it has been shown that altered joint biomechanics of the knee, such as loss of cruciate ligaments, removal of menisci, posttraumatic cartilage damage, changes in bone alignments, unloading through casting and overloading through intense exercise may cause disease initiation and progression of cartilage degradation. […] The mechanical axis or alignment of the lower extremity is defined as a line drawn from the centre of the femoral head to the centre of the talus.
#18 Biomechanics and pathomechanisms ofÂ osteoarthritis
https://smw.ch/index.php/smw/article/download/1523/1931
These findings arouse the suspicion that AdM is an important determinant but not the only one in the multifactorial disease of OA. […] The symptomatic stage in knee and ankle OA typically occurs when patients are in their economically important active middle ages, because trauma is the predominant cause of their OA. […] The efficacy of realignment surgery to restore almost normo-biomechanics has been shown to relieve pain and improve function. […] These data indicate that realignment surgery is a powerful tool to realign biomechanical loading forces across the joint with subsequent bone reaction. […] OA and biomechanics are inescapably linked together. […] However, the contribution of biomechanical factors to aetiology, pathogenesis and to disease progression require further research in order to reduce the enormous socioeconomic and personal impact of this disease.
#19 Current understanding of osteoarthritis pathogenesis and relevant new approaches | Bone Research
https://www.nature.com/articles/s41413-022-00226-9
Osteoarthritis (OA) is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body. The molecular mechanisms of OA are currently unknown. OA is a heterogeneous disease that affects the entire joint, and multiple tissues are altered during OA development. To better understand the pathological mechanisms of OA, new approaches, methods, and techniques need to be used to understand OA pathogenesis. […] The pathological mechanisms of OA are currently unknown. Epigenetic regulation is a newly emerging area associated with alterations in catabolic and anabolic gene expression in osteoarthritic chondrocytes. […] Recent findings have provided new insights into the roles of new forms of regulated cell death and the synovial lymphatic system in the pathogenesis of OA.
#20 Current understanding of osteoarthritis pathogenesis and relevant new approaches | Bone Research
https://www.nature.com/articles/s41413-022-00226-9
First, we focused on the epigenetic regulation of OA, with a particular focus on DNA methylation, histone modification, and microRNA regulation, which have been implicated in OA, and potential epigenome-based therapeutics for OA, followed by a summary of several key mediators in OA-associated pain, including NGF, CGRP, CCL2/CCR2, and TNF. […] Overall, recent studies showed the critical role of DNMTs in OA development and suggested that DNMTs may be new molecular targets for OA treatment in the clinic. […] These findings suggest that histone methylation is involved in OA pathogenesis through the regulation of anabolic and catabolic activities in chondrocytes. […] Significant progress has been achieved in clarifying the role of Sirtuin 1 (SIRT1) in OA pathological progression. […] These studies suggest that SIRT1 activation may serve as an ideal therapeutic strategy for OA treatment.
#21 Current understanding of osteoarthritis pathogenesis and relevant new approaches | Bone Research
https://www.nature.com/articles/s41413-022-00226-9
These findings demonstrated that miRNAs are closely associated with the regulation of OA development and progression. […] The synovial lymphatic system plays an important role in the clearance of cartilage-derived catabolic factors in the synovium of OA joints, which opens up novel research directions. […] Despite the significant progress in our understanding of OA pathogenesis, the etiology and pathological mechanisms of OA are not yet fully understood.
#22 Senescence in osteoarthritis: from mechanism to potential treatment | Arthritis Research & Therapy | Full Text
https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-022-02859-x
Osteoarthritis (OA) is an age-related cartilage degenerative disease, and chondrocyte senescence has been extensively studied in recent years. Increased numbers of senescent chondrocytes are found in OA cartilage. […] The inflammatory environment induced by SASP factors is involved in cartilage degeneration and subchondral bone remodelling and eventually leads to cartilage loss and OA progression. […] Although the specific mechanism of cellular senescence in OA is unclear, the selective clearance of senescent cells in osteoarthritic mice can attenuate the development of post-traumatic OA (PTOA), while intraarticular injection of senescent cells induced mouse OA. […] The senescent microenvironment in the osteoarthritic joint includes not only senescent chondrocytes, but also synovial fibroblasts and synovial macrophages.
#23 Senescence in osteoarthritis: from mechanism to potential treatment | Arthritis Research & Therapy | Full Text
https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-022-02859-x
The mechanisms leading to senescence are numerous and complicated. […] Mechanical overloading promoted senescence in vitro in cultured chondrocytes and in mouse cartilage. […] Senescent cells produce SASP factors, which promote the inflammatory microenvironment and cartilage catabolism. […] Mechanical stress and ageing are two main risk factors for OA, both of which are capable of producing ROS and oxidative stress. […] Mitochondrial dysfunction and oxidative stress are key factors in OA. […] The production of SASPs is not only a characteristic of senescent chondrocytes. […] In addition, senescent cells can release SASPs into their surroundings, which exerts a chemotactic effect on immune cells. […] The senolytic drug UBX0101 failed to outperform the placebo in a phase II clinical trial. […] Immunotherapy in OA is rather new and shows potential, as it is naturally in accordance with establishing normal homeostasis in old and young cells.
#24 Hundreds of genetic links to osteoarthritis unlocked in landmark study | News | The University of Sheffield
https://www.sheffield.ac.uk/news/hundreds-genetic-links-osteoarthritis-unlocked-landmark-study
Over 900 genetic links to osteoarthritis, including 500 that have never been reported before, have been uncovered in breakthrough research from the University of Sheffield. […] By integrating diverse biomedical datasets, the researchers from the University of Sheffield and Sheffield Teaching Hospitals Foundation Trust, also identified 700 genetic disease-associated variants that were implicated in the development of osteoarthritis. Eight biological processes involved in regulating the body’s internal systems and cell function were also discovered, shedding light on the biological mechanism of the disease. These include both the circadian clock and development signalling pathways. […] As well as identifying potential drug targets and opportunities for us to repurpose existing treatments that already target these genes in other conditions, this research has also significantly advanced our understanding of the underlying biological mechanisms associated with the disease.
#25 Current understanding of osteoarthritis pathogenesis and relevant new approaches
https://www.sciopen.com/article/10.1038/s41413-022-00226-9
Next, we discuss the timely updates concerning cell death regulation in OA pathology, including pyroptosis, ferroptosis, and autophagy, as well as their individual roles in OA and potential molecular targets in treating OA. […] An improved understanding of OA pathogenesis will aid in the development of more specific and effective therapeutic interventions for OA. […] The epigenomic landscape in osteoarthritis. […] DNA methylation in osteoarthritic chondrocytes: a new molecular target. […] Inflammation and epigenetic regulation in osteoarthritis. […] The role of metabolism in the pathogenesis of osteoarthritis. […] Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. […] Chondrocyte ferroptosis contribute to the progression of osteoarthritis. […] Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx. […] Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. […] The role of synovial lymphatic function in osteoarthritis.
#26 Is interleukin-17 implicated in early knee osteoarthritis pathogenesis as in rheumatoid arthritis? | Egyptian Rheumatology and Rehabilitation | Full Text
https://erar.springeropen.com/articles/10.1186/s43166-022-00130-4
Interleukin-17 (IL-17) is a cytokine that promotes activation of multiple catabolic pathways resulting in cartilage and tissue damage. […] The increased serum IL-17 level in patients with early knee OA suggests its pathogenic role in the disease. […] Knee osteoarthritis (OA) is a disease with a high prevalence in our community. It is often associated with low-grade synovitis that contributes to increased joint pain and dysfunction and, significantly, a more rapid progression of structural joint deterioration. […] Several proofs suggest that IL-17A has a role in OA pathophysiology and IL-17-treated chondrocytes from OA patients showed enhanced expression of catabolic factors that are involved in the destruction of cartilage in OA. […] In this study, the mean serum IL-17 level concentration in early KOA group was 5.2 (2.66.6) pg/ml, significantly higher than in the controls 4.9 (0.45.1) pg/ml but not reaching those levels in studied RA patients 5.9 (5.39.9) pg/ml.
#27 Is interleukin-17 implicated in early knee osteoarthritis pathogenesis as in rheumatoid arthritis? | Egyptian Rheumatology and Rehabilitation | Full Text
https://erar.springeropen.com/articles/10.1186/s43166-022-00130-4
Serum IL-17 level in those patients was correlated with KOOS functional score. It was found that it was positively correlated with KOOS pain subscale score. […] This study further confirms the role of IL-17 in RA pathogenesis and the lack of IL-17 correlation with RA disease activity. In knee OA, IL-17 seems to have a pathogenic role.
#28 Study Identifies Mechanism Underlying Increased Osteoarthritis Risk in Postmenopausal Females
https://spauldingrehab.org/about/news/study-identifies-mechanism-underlying-increased-osteoarthritis-risk-in-postmenopausal-females
A new study by Spaulding Rehabilitation researchers provides critical insights into the relationship between menopause and osteoarthritis, a condition that affects millions of postmenopausal women. […] While the hormonal changes associated with menopause have long been known to accelerate the development and progression of OA, a deeper understanding of the biological mechanisms that underlie this correlation is crucial for developing effective treatments. […] By understanding how menopause-induced changes in sex hormone levels contribute to joint degeneration, our hope is that this will pave the way for researchers to develop novel strategies that slow or prevent the progression of OA, which could lead to a better quality of life for millions of women worldwide. […] The changes observed mirrored those seen in humans, with cartilage quality loss occurring at the start of menopause, similar to clinical reports.
#29 Study Identifies Mechanism Underlying Increased Osteoarthritis Risk in Postmenopausal Females
https://spauldingrehab.org/about/news/study-identifies-mechanism-underlying-increased-osteoarthritis-risk-in-postmenopausal-females
They discovered that menopause-induced loss of estrogen and progesterone promotes extracellular matrix degradation and chondrocyte deterioration, while restoring these hormones to pre-menopausal levels protected against cartilage degeneration. […] This research provides insights into why the long-observed sex differences in osteoarthritis rates may occur.
#30
https://insight.jci.org/articles/view/173603/figure/4
Dysregulated fibrinolysis and plasmin activation promote the pathogenesis of osteoarthritis. […] Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis. […] Here, we showed that the fibrinolytic pathway, which includes plasminogen/plasmin, tissue plasminogen activator, urokinase plasminogen activator (uPA), and the uPA receptor (uPAR), was dysregulated in human OA joints. […] Pharmacological inhibition of plasmin attenuated OA progression after a destabilization of the medial meniscus in a mouse model whereas genetic deficiency of plasmin activator inhibitor, or injection of plasmin, exacerbated OA. […] In vitro studies identified that plasmin promotes OA development through multiple mechanisms, including the degradation of lubricin and cartilage proteoglycans and induction of inflammatory and degradative mediators.
#31
https://insight.jci.org/articles/view/173603/figure/4
Together, we demonstrated that fibrinolysis contributes to the development of OA through multiple mechanisms and suggested that therapeutic targeting of the fibrinolysis pathway can prevent or slow development of OA. […] Plasmin contributes to the initiation and progression of OA through multiple mechanisms: the degradation of lubricin and cartilage proteoglycan, activation of pro-MMPs, and induction of inflammatory and degradative mediators from synovial cells.
#32 Pathogenesis of Osteoarthritis | Department of Orthopaedic Surgery – Lin Laboratory | University of Pittsburgh
https://www.linlab.pitt.edu/projects/pathogenesis-osteoarthritis
Osteoarthritis (OA) is a painful and disabling disease that affects millions of people worldwide. […] Furthermore, there are currently no disease-modifying OA drugs (DMOADs) with demonstrated efficacy in OA patients, which is, in part, attributed to a lack of full understanding of the pathogenesis of OA. […] Mitochondrial dysfunction has also been observed in osteoarthritic chondrocytes. […] Currently, there are no therapies that can halt or reverse the progression of osteoarthritis (OA). […] Taken together, our study demonstrates a new estrogen-independent role of ER in mediating chondrocyte phenotype and response to mechanical loading, and suggests that enhancing ER level may represent a new method to treat osteoarthritis.
#33 OA-HybridCNN (OHC): An advanced deep learning fusion model for enhanced diagnostic accuracy in knee osteoarthritis imaging | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0322540
Osteoarthritis (OA) is a degenerative joint disorder presenting with cartilage damage, subchondral bone remodeling, osteophyte formation, alterations in the joint capsule, and synovial inflammation. […] The early diagnosis, timely identification, and intervention for KOA hold the potential to slow down, halt, or even reverse the disease, significantly enhancing patient prognosis and quality of life. […] Currently, the diagnosis of osteoarthritis primarily relies on the patient’s medical history, clinical symptoms, and medical imaging. […] Presently, the widely accepted diagnostic criteria for knee osteoarthritis are the Kellgren-Lawrence (KL) grading system and the atlas provided by the Osteoarthritis Research Society International (OARSI). […] In recent years, the rapid development of artificial intelligence has found widespread applications in the intelligent recognition and auxiliary diagnosis of osteoarthritis.
#34 Pathogenesis of osteoarthritis – UpToDate
https://www.uptodate.com/contents/pathogenesis-of-osteoarthritis/print
Pathogenesis of osteoarthritis […] However, the pathogenesis of OA is much more complex than just wear and tear and the term „osteoarthritis,” where „-itis” is indicative of an inflammatory process, is indeed correct. There are a variety of factors that play an important role in the pathogenesis of OA, including biomechanical factors, proinflammatory mediators, and proteases. By understanding the mechanisms driving joint tissue destruction in OA and identifying the key factors involved, new targets for therapy are emerging that will go beyond symptomatic relief to slowing or stopping the progression of OA.
#35 RANK-L Activity: Understanding the Pathogenesis of Erosive Osteoarthritis – ACR Meeting Abstracts
https://acrabstracts.org/abstract/rank-l-activity-understanding-the-pathogenesis-of-erosive-osteoarthritis/
RANK-L Activity: Understanding the Pathogenesis of Erosive Osteoarthritis […] Erosive osteoarthritis (EOA) is characterized by osteoarthritic findings with central erosions and collapse of the interphalangeal joint subchondral bone plate. A number of studies indicate that there is an inflammatory component but the pathophysiology of the erosions is not known. Receptor activator of nuclear factor kappa-B ligand (RANK-L) is involved in the erosive process of inflammatory arthritides and we hypothesized that it would be involved in the erosive process of EOA. […] Our study demonstrated that EOA patients had higher levels of RANK-L in synovial tissue and were with lower BMD scores than patients with OA. We therefore propose that RANK-L activity promotes the osteoclastic driven erosive changes in EOA and also results in systemic bone loss.
#36 Estrogen-related receptor γ is a novel catabolic regulator of osteoarthritis pathogenesis
https://www.bmbreports.org/journal/view.html?uid=1240
Osteoarthritis (OA) is the most common form of arthritis and is a leading cause of disability with a large socioeconomic cost. OA is a whole-joint disease characterized by cartilage destruction, synovial inflammation, osteophyte formation, and subchondral bone sclerosis. To date, however, no effective disease-modifying therapies for OA have been developed. […] The estrogen-related receptors (ERRs), a family of orphan nuclear receptor transcription factors, are composed of ERR, ERR, and ERR, which play diverse biological functions such as cellular energy metabolism. However, the role of ERRs in OA pathogenesis has not been studied yet. Among the ERR family members, ERR is markedly upregulated in human and various models of mouse OA cartilage. […] These results collectively indicated that ERR is a novel catabolic regulator of OA pathogenesis and can be used as a therapeutic target for OA.
#37 Estrogen-related receptor γ is a novel catabolic regulator of osteoarthritis pathogenesis
https://www.bmbreports.org/journal/view.html?uid=1240
Thus, these gain-of-function studies collectively indicate that ERR is a catabolic regulator of OA pathogenesis. […] These results collectively indicate that knockdown or genetic ablation of Esrrg in mice inhibits OA pathogenesis caused by DMM surgery. […] Collectively, these results are the first to demonstrate that ERR acts as a catabolic regulator of cartilage degeneration and OA pathogenesis, and support the idea that ERR could be a therapeutic target for OA.
#38 New Mechanism Uncovered Behind Osteoarthritis Could Inform New Treatments
https://spauldingrehab.org/about/news/osteoarthritis-mechanism-could-inform-new-treatments
Researchers in the United States and Japan have discovered a new mechanism that links age-related cartilage tissue stiffening with the repression of a key protein associated with longevity. These findings enhance the understanding of mechanisms that lead to the deterioration of joints that causes osteoarthritis, according to the authors of a new study, published January 10th in Nature Communications. […] As stiffening of extracellular matrix is a defining feature of cartilage aging, these findings demonstrate the role Klotho plays in the formation of osteoarthritis and offers new potential treatment targets to restore cartilage health. […] This research enhances our mechanistic understanding of why osteoarthritis happens in the first place, and it paves the way for the development of therapeutics to prevent these changes.
#39 New Mechanism Uncovered Behind Osteoarthritis Could Inform New Treatments
https://spauldingrehab.org/about/news/osteoarthritis-mechanism-could-inform-new-treatments
Osteoarthritis occurs when cartilage in a joint stiffens and begins to break down which then damages the underlying bone, resulting in pain, swelling and feelings of stiffness. […] There are currently no treatments to reverse this cartilage stiffening and resulting damage. […] The researchers found that Klotho was heavily involved in the molecular process that led to osteoarthritis. […] The new analysis revealed that when knee cartilage tissue became stiffer, the gene that codes for Klotho was repressed. […] These results provide a compelling new paradigm that will be important for the field in terms of understanding the connection between age-related tissue stiffening and risk for osteoarthritis with aging. […] With the latest findings, the researchers plan to study whether there are ways to intervene with the disease process that leads to osteoarthritis, such as by blocking the pathway that represses Klotho, even in the face of a stiff extracellular matrix environment.
#40 Pathogenesis of Osteoarthritis: Risk Factors, Regulatory Pathways in Chondrocytes, and Experimental Models – D-Scholarship@Pitt
https://d-scholarship.pitt.edu/41151/
As the most common chronic degenerative joint disease, osteoarthritis (OA) is the leading cause of pain and physical disability, affecting millions of people worldwide. Mainly characterized by articular cartilage degradation, osteophyte formation, subchondral bone remodeling, and synovial inflammation, OA is a heterogeneous disease that impacts all component tissues of the articular joint organ. […] In this review, we provide an update of the known OA risk factors and relevant mechanisms of action. […] given that the lack of biologically relevant models to recapitulate human OA pathogenesis represents one of the major roadblocks in developing DMOADs, we discuss current in vivo and in vitro experimental OA models, with special emphasis on recent development and application potential of human cell-derived microphysiological tissue chip platforms.
#41 Modelling Osteoarthritis pathogenesis through Mechanical Loading in an Osteochondral Unit-on-Chip | bioRxiv
https://www.biorxiv.org/content/10.1101/2023.08.29.555292v1
A cure for osteoarthritis (OA), the most prevalent musculoskeletal disease, remains an unmet need. Investigating the molecular and cellular processes leading to OA is challenged by the absence of human models that capture the complex interplay among different tissues in the joint under pathophysiological mechanical loading. […] In this study, we have engineered an OsteoChondral Unit (OCU)-on-chip system where composite hyaline cartilage – mineralized osseous microtissue analogues are exposed to controlled, tissue-specific compression regimes akin to those of the OCU in vivo. Through single-cell transcriptomic analysis, we demonstrate the critical relevance of the mineralized layer in inducing chondrocyte subpopulations implicated in the progression of OA. […] Upon exposure to hyperphysiological loading, the OCU-on-chip captures early phenotypic traits of OA pathogenesis, comprising alterations of subchondral mineral content and acquisition of previously described OA genetic signatures. […] This system enabled to identify novel upstream drivers of OA metabolic changes, including mechanically induced ribosomal alterations, as well as associated molecular targets towards the development of disease-modifying OA therapies.
#42 Current understanding of osteoarthritis pathogenesis and relevant new approaches
https://www.sciopen.com/article/10.1038/s41413-022-00226-9
Osteoarthritis (OA) is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body. The molecular mechanisms of OA are currently unknown. OA is a heterogeneous disease that affects the entire joint, and multiple tissues are altered during OA development. To better understand the pathological mechanisms of OA, new approaches, methods, and techniques need to be used to understand OA pathogenesis. […] We first focus on the epigenetic regulation of OA, with a particular focus on DNA methylation, histone modification, and microRNA regulation, followed by a summary of several key mediators in OA-associated pain. […] We then introduce several innovative techniques that have been and will continue to be used in the fields of OA and OA-associated pain, such as CRISPR, scRNA sequencing, and lineage tracing.
#43 Pathogenesis of Osteoarthritis: Risk Factors, Regulatory Pathways in Chondrocytes, and Experimental Models
https://www.mdpi.com/resolver?pii=biology9080194
Pathological changes, and thus symptoms, vary from person to person, underscoring the critical need of personalized therapies. […] However, there has only been limited progress towards the prevention and treatment of OA, and there are no approved effective disease-modifying osteoarthritis drugs (DMOADs). […] In OA, dysregulation caused by the presence of various biofactors leads to the loss of cartilage homeostasis, resulting in degradation of the collagen- and proteoglycan-rich extracellular matrix (ECM), fibrillation and erosion of the articular surface, cell death, matrix calcification, and vascular invasion. […] Despite the disease being known for centuries, the exact pathogenic mechanisms of OA remain unclear. […] Most cases of OA have a clear predisposing condition, such as genetics, trauma, aging, or obesity, leading to the idea that OA describes a common endpoint with different etiologies.
#44 Pathogenesis of Osteoarthritis: Risk Factors, Regulatory Pathways in Chondrocytes, and Experimental Models
https://www.mdpi.com/2079-7737/9/8/194
Pathological changes, and thus symptoms, vary from person to person, underscoring the critical need of personalized therapies. […] However, detailed examination revealed patient-specific variability in the clinical presentation and disease progression. […] In any case, it is now widely accepted that OA is a dynamic and complex process, involving inflammatory, mechanical, and metabolic factors that result in the inability of the articular surface to serve its function of absorbing and distributing the mechanical load through the joint that ultimately leads to joint destruction. […] Furthermore, it is now recognized that the disease is not restricted to the cartilage or subchondral bone; rather, it results from interplay among tissues of the osteochondral complex, including adipose and synovial tissue, as well as the ligaments, tendon, and muscles that surround the joint.
#45 Re-thinking osteoarthritis pathogenesis: what can we learn (and what do we need to unlearn) from mouse models about the mechanisms involved in disease development | Arthritis Research & Therapy | Full Text
https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-023-03042-6
Efforts to develop effective disease-modifying drugs to treat osteoarthritis have so far proved unsuccessful with a number of promising drug candidates from pre-clinical studies failing to show efficacy in clinical trials. It is therefore timely to re-evaluate our current understanding of osteoarthritis pathogenesis and the similarities and differences in disease development between commonly used pre-clinical mouse models and human patients. There is substantial heterogeneity between patients presenting with osteoarthritis and mounting evidence that the pathways involved in osteoarthritis (e.g. Wnt signalling) differ between patient sub-groups. […] There is also emerging evidence that the pathways involved in osteoarthritis differ between the STR/ort mouse model (the most extensively studied mouse model of spontaneously occurring osteoarthritis) and injury-induced osteoarthritis mouse models. For instance, while canonical Wnt signalling is upregulated in the synovium and cartilage at an early stage of disease in injury-induced osteoarthritis mouse models, this does not appear to be the case in the STR/ort mouse. Such findings may prove insightful for understanding the heterogeneity in mechanisms involved in osteoarthritis pathogenesis in human disease. However, it is important to recognise that there are differences between mice and humans in osteoarthritis pathogenesis. A much more extensive array of pathological changes are evident in osteoarthritic joints in individual mice with osteoarthritis compared to individual patients. There are also specified differences in the pathways involved in disease development. For instance, although increased TGF- signalling is implicated in osteoarthritis development in both mouse models of osteoarthritis and human disease, in mice, this is mainly mediated through TGF-3 whereas in humans, it is through TGF-1. […] Understanding the similarities and differences in osteoarthritis pathogenesis between mouse models and humans is critical for understanding the translational potential of findings from pre-clinical studies.