ROR2 blockade as a therapy for osteoarthritis

Abstract

Osteoarthritis is characterized by the loss of the articular cartilage, bone remodeling, pain, and disability. No pharmacological intervention can currently halt progression of osteoarthritis. Here, we show that blocking receptor tyrosine kinase–like orphan receptor 2 (ROR2) improves cartilage integrity and pain in osteoarthritis models by inhibiting yes-associated protein (YAP) signaling. ROR2 was up-regulated in the cartilage in response to inflammatory cytokines and mechanical stress. The main ligand for ROR2, WNT5A, and the targets YAP and connective tissue growth factor were up-regulated in osteoarthritis in humans. In vitro, ROR2 overexpression inhibited chondrocytic differentiation. Conversely, ROR2 blockade triggered chondrogenic differentiation of C3H10T1/2 cells and suppressed the expression of the cartilage-degrading enzymes a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)–4 and ADAMTS-5. The chondrogenic effect of ROR2 blockade in the cartilage was independent of WNT signaling and was mediated by down-regulation of YAP signaling. ROR2 signaling induced G protein and Rho-dependent nuclear accumulation of YAP, and YAP inhibition was required but not sufficient for ROR2 blockade–induced chondrogenesis. ROR2 silencing protected mice from instability-induced osteoarthritis with improved structural outcomes, sustained pain relief, and without apparent side effects or organ toxicity. Last, ROR2 silencing in human articular chondrocytes transplanted in nude mice led to the formation of cartilage organoids with more and better differentiated extracellular matrix, suggesting that the anabolic effect of ROR2 blockade is conserved in humans. Thus, ROR2 blockade is efficacious and well tolerated in preclinical animal models of osteoarthritis.

Mechanoregulation of YAP and TAZ in Cellular Homeostasis and Disease Progression

“…OA is mainly caused by mechanical overload ( Glyn-Jones et al, 2015 ), and it has been reported that YAP is both necessary and adequate to preserve cartilage homeostasis in OA ( Deng et al, 2018 ; Zhang Q. et al, 2019 ). A few recent studies demonstrated that suppressing YAP activity is effective in attenuating OA progression ( Gong et al, 2019 ; Thorup et al, 2020 ; Zhang et al, 2020 ). However, research is still lacking on how the mechanical forces, especially compression and hydrostatic pressure, regulate Hippo-YAP/TAZ pathway in chondrocytes in healthy cartilage and during OA development.…”

Tyrosine kinases regulate chondrocyte hypertrophy: promising drug targets for Osteoarthritis

“…ROR2 inhibition in primary human chondrocytes suppressed expression of ADAMTS4/5 and increased SOX9. Furthermore, blocking ROR2 in a mouse OA model reduce pain and cartilage damage 35 . This study suggests that ROR2 is associated with WNT5A and hypertrophy and thus, ROR2 could also be a potential target for OA.…”

Glucosamine as a Treatment for Osteoarthritis: What If It’s True?

“…On the other hand, if the diagnosis is made early, developing treatments to slow the progression of joint degradation is a reasonable goal. Thanks to recent achievements in understanding the causes of the cartilage degradation many therapeutic approaches are now being investigated ( Hochberg et al, 2019 ; Ghouri and Conaghan, 2019 ; Stevens et al, 2019 ; Thorup et al, 2020 ; Yazici et al, 2020 ; Fernández-Martín et al, 2021 ). However, we cannot hope for a structure-modifying treatment to be marketed for several years.…”