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- Title
ITGBL1 modulates integrin activity to promote cartilage formation and protect against arthritis.
- Authors
Song, Eun Kyung; Jeon, Jimin; Jang, Dong Gil; Kim, Ha Eun; Sim, Hyo Jung; Kwon, Keun Yeong; Medina-Ruiz, Sofia; Jang, Hyun-Jun; Lee, Ah Reum; Rho, Jun Gi; Lee, Hyun-Shik; Kim, Seok Jung; Park, Chan Young; Myung, Kyungjae; Kim, Wook; Kwon, Taejoon; Yang, Siyoung; Park, Tae Joo
- Abstract
ITGBL1 promotes chondrogenesis and protects joint cartilage from osteoarthritis by inhibiting integrin-extracellular matrix interaction. Defense against joint degeneration: Chondrocytes secrete and become embedded in condensed extracellular matrix (ECM) during cartilage development. In joint disease such as osteoarthritis (OA), dysregulation of this process leads to degradation of the ECM. Song et al. found reduced expression of integrin-β–like 1 (ITGBL1), a secreted integrin inhibitory protein expressed during cartilage development, in samples of cartilage from patients with OA. ITGBL1 inhibited integrin-ECM interactions and promoted chondrogenic differentiation in cells. ITGBL1 depletion reduced ECM deposition and led to cartilage damage, whereas overexpression of ITGBL1 prevented knee joint degeneration in a mouse model of surgically induced OA. This study identifies a target to modulate integrin signaling, which could have potential therapeutic effects for OA. Developing and mature chondrocytes constantly interact with and remodel the surrounding extracellular matrix (ECM). Recent research indicates that integrin-ECM interaction is differentially regulated during cartilage formation (chondrogenesis). Integrin signaling is also a key source of the catabolic reactions responsible for joint destruction in both rheumatoid arthritis and osteoarthritis. However, we do not understand how chondrocytes dynamically regulate integrin signaling in such an ECM-rich environment. Here, we found that developing chondrocytes express integrin-β–like 1 (Itgbl1) at specific stages, inhibiting integrin signaling and promoting chondrogenesis. Unlike cytosolic integrin inhibitors, ITGBL1 is secreted and physically interacts with integrins to down-regulate activity. We observed that Itgbl1 expression was strongly reduced in the damaged articular cartilage of patients with osteoarthritis (OA). Ectopic expression of Itgbl1 protected joint cartilage against OA development in the destabilization of the medial meniscus–induced OA mouse model. Our results reveal ITGBL1 signaling as an underlying mechanism of protection against destructive cartilage disorders and suggest the potential therapeutic utility of targeting ITGBL1 to modulate integrin signaling in human disease.
- Subjects
CARTILAGE diseases; CARTILAGE cells; EXTRACELLULAR matrix; INTEGRINS; XENOPUS
- Publication
Science Translational Medicine, 2018, Vol 10, Issue 462, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aam7486