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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 α(V)β(3) 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 α(V)β(3), CD47, and their ligands. Using genetically deficient mice and pharmacologic inhibitors, we showed that α(V)β(3), 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 α(V)β(3) and CD47 in osteoarthritic joints. Further, our in vitro studies demonstrated that chondrocyte breakdown products, derived from articular cartilage of individuals with OA, induced α(V)β(3)/CD47-dependent expression of inflammatory and degradative mediators, and revealed the downstream signaling network. Our findings identify a central role for dysregulated α(V)β(3) and CD47 signaling in OA pathogenesis and suggest that activation of α(V)β(3) 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 α(V)β(3), CD47, and their signaling pathways as a disease-modifying therapy.

A key question in studies of mass extinctions is whether the extinction was a sudden or gradual event. This question may be addressed by examining the locations of fossil occurrences in a stratigraphic section. However, the fossil record can be consistent with both sudden and gradual extinctions. Rather than being limited to rejecting or not rejecting a particular scenario, ideally we should estimate therangeof extinction scenarios that is consistent with the fossil record. In other words, rather than testing the simplified distinction of “sudden versus gradual,” we should be asking, “How gradual?”In this paper we answer the question “How gradual could the extinction have been?” by developing a confidence interval for the duration of a mass extinction. We define the duration of the extinction as the time or stratigraphic thickness between the first and last taxon to go extinct, which we denote by Δ. For example, we would like to be able to say with 90% confidence that the extinction took place over a duration of 0.3 to 1.1 million years, or 24 to 57 meters of stratigraphic thickness. Our method does not deny the possibility of a truly simultaneous extinction; rather, in this framework, a simultaneous extinction is one whose value of Δ is equal to zero years or meters.We present an algorithm to derive such estimates and show that it produces valid confidence intervals. We illustrate its use with data from Late Permian ostracodes from Meishan, China, and Late Cretaceous ammonites from Seymour Island, Antarctica.