Research ArticleOsteoarthritis

ROR2 blockade as a therapy for osteoarthritis

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Science Translational Medicine  16 Sep 2020:
Vol. 12, Issue 561, eaax3063
DOI: 10.1126/scitranslmed.aax3063

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Countering cartilage breakdown

Receptor tyrosine kinase–like orphan receptor 2 (ROR2) is expressed in the cartilage during development. Here, Thorup et al. found that ROR2 signaling was increased in damaged osteoarthritic cartilage tissue and that its overexpression inhibited chondrocyte differentiation. Blocking ROR2 in a mouse model of surgically induced osteoarthritis lessened pain and improved joint architecture, and silencing ROR2 in cells promoted formation of the healthy cartilage. Results suggest that ROR2 could be a potential therapeutic target 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.

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