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<p>Collagen XXIV (Col24&#945;1) is a recently discovered fibrillar collagen. It is known that mouse Col24&#945;1 is predominantly expressed in the forming skeleton of the mouse embryo, as well as in the trabecular bone and periosteum of the newborn mouse. However, the role and mechanism of Col24&#945;1 in osteoblast differentiation and mineralization remains unclear. By analyzing the expression pattern of Col24&#945;1, we confirmed that it is primarily expressed in bone tissues, and this expression gradually increased concomitant with the progression of osteoblast differentiation. Through the use of a lentivirus vector-mediated interference system, silencing Col24&#945;1 expression in MC3T3-E1 murine preosteoblastic cells resulted in significant inhibition of alkaline phosphatase (ALP) activity, cell mineralization, and the expression of osteoblast marker genes such as runt-related transcription factor 2 (Runx2), osteocalcin (OCN), ALP, and type I collagen (Col I). Subsequent overexpression not only rescued the deficiency in osteoblast differentiation from Col24&#945;1 silenced cells, but also enhanced osteoblastic differentiation in control cells. We further revealed that Col24&#945;1 interacts with integrin &#946;3, and silencing Col24&#945;1 up-regulated the expression of Smad7 during osteoblast differentiation while at the same time inhibiting the phosphorylation of the Smad2/3 complex. These results suggest that Col24&#945;1 imparts some of its regulatory control on osteoblast differentiation and mineralization at least partially through interaction with integrin &#946;3 and the transforming growth factor beta (TGF-&#946;) /Smads signaling pathway.</p>