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JCI Insight. 2019 Sep 19;4(18). pii: 128616. doi: 10.1172/jci.insight.128616.

Dysregulated integrin αVβ3 and CD47 signaling promotes joint inflammation, cartilage breakdown, and progression of osteoarthritis.

Author information

1
Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.
2
Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.
3
Molecular Imaging Program at Stanford (MIPS), Canary Center at Stanford for Cancer Early Detection, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California, USA.
4
Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do, South Korea.
5
Department of Orthopedic Surgery.
6
Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, and.
7
Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.

Abstract

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 αVβ3 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 αVβ3, CD47, and their ligands. Using genetically deficient mice and pharmacologic inhibitors, we showed that αVβ3, 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 αVβ3 and CD47 in osteoarthritic joints. Further, our in vitro studies demonstrated that chondrocyte breakdown products, derived from articular cartilage of individuals with OA, induced αVβ3/CD47-dependent expression of inflammatory and degradative mediators, and revealed the downstream signaling network. Our findings identify a central role for dysregulated αVβ3 and CD47 signaling in OA pathogenesis and suggest that activation of αVβ3 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 αVβ3, CD47, and their signaling pathways as a disease-modifying therapy.

KEYWORDS:

Cartilage; Immunology; Inflammation; Integrins; Osteoarthritis

PMID:
31534047
DOI:
10.1172/jci.insight.128616
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