| First Author | Wang Q | Year | 2019 |
| Journal | JCI Insight | Volume | 4 |
| Issue | 18 | PubMed ID | 31534047 |
| Mgi Jnum | J:296784 | Mgi Id | MGI:6468820 |
| Doi | 10.1172/jci.insight.128616 | Citation | Wang Q, et al. (2019) Dysregulated integrin alphaVbeta3 and CD47 signaling promotes joint inflammation, cartilage breakdown, and progression of osteoarthritis. JCI Insight 4(18) |
| abstractText | Osteoarthritis (OA) is the leading cause of joint failure, yet the underlying mechanisms remain elusive, and no approved therapies that slow progression exist. Dysregulated integrin function was previously implicated in OA pathogenesis. However, the roles of integrin alphaVbeta3 and the integrin-associated receptor CD47 in OA remain largely unknown. Here, transcriptomic and proteomic analyses of human and murine osteoarthritic tissues revealed dysregulated expression of alphaVbeta3, CD47, and their ligands. Using genetically deficient mice and pharmacologic inhibitors, we showed that alphaVbeta3, CD47, and the downstream signaling molecules Fyn and FAK are crucial to OA pathogenesis. MicroPET/CT imaging of a mouse model showed elevated ligand-binding capacities of integrin alphaVbeta3 and CD47 in osteoarthritic joints. Further, our in vitro studies demonstrated that chondrocyte breakdown products, derived from articular cartilage of individuals with OA, induced alphaVbeta3/CD47-dependent expression of inflammatory and degradative mediators, and revealed the downstream signaling network. Our findings identify a central role for dysregulated alphaVbeta3 and CD47 signaling in OA pathogenesis and suggest that activation of alphaVbeta3 and CD47 signaling in many articular cell types contributes to inflammation and joint destruction in OA. Thus, the data presented here provide a rationale for targeting alphaVbeta3, CD47, and their signaling pathways as a disease-modifying therapy. |
