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.
Tetrasubstituted
carbon containing two different halogen substituents was constructed
in a single-step operation by utilizing the carbene-like reactivity
of dioxaphospholene through the tandem reaction of electrophilic and
nucleophilic halogenating reagents. It was crucial to devise non-dealkylatable
phosphoramidite, which enabled the efficient formation of geminal
chlorofluorides from various 1,2-diketones with (PhSO2)2NF and n-Bu4NCl. In addition,
selective functionalization of the chlorine substituent was demonstrated,
and the absence of halogen scrambling was confirmed.
VV-ECMO support can be a feasible rescue strategy for adult patients who develop refractory ARDS after a cardiac surgery. Additionally, the RESP score seems a valuable prognostic tool for post-ECMO survival outcome in this patient population as well.
We characterize the extent to which Black-White gaps for multiple educational outcomes are linked across school districts in the United States. Gaps in disciplinary action, grade-level retention, classification into special education and Gifted and Talented, and Advanced Placement course-taking are large in magnitude and correlated. Racial differences in family income and parent education are strikingly consistent predictors of these gaps, and districts with large gaps in one outcome are likely to have large gaps in another. Socioeconomic and segregation variables explain 1.7 to 3.5 times more variance for achievement relative to nonachievement outcomes. Systemic patterns of racial socioeconomic inequality drive inequalities across multiple educational outcomes; however, discretionary policies at local levels are more influential for nonachievement outcomes.
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