Original Full Length ArticleDifferential development of the distal and proximal femoral epiphysis and physis in mice

Many pathologic conditions of hip development result from aberrant vascularity with subsequent effects on physeal resorption and epiphyseal fusion. To elucidate the mechanisms of these developmental disorders, researchers have mainly focused on larger mammals as they have been well characterized and are known to provide a model similar to humans in which a secondary ossification center is formed through an independent blood supply followed by physeal resorption. Murine models of hip development, however, have never been characterized as it was previously assumed that all physes in rodents never resorb and therefore not suitable as a model of the human condition. The purpose of this study was to determine if murine hip development was comparable to humans as laboratory mice provide an ideal model in which genetic knockouts are readily available with a short developmental time span. Here we show for the first time the unique developmental patterns of the murine hip in which a secondary ossification center never develops. Instead, the epiphysis undergoes a prolonged phase of mineralization through chondrocyte, not osteoblast, dependent mechanisms. After skeletal growth, transphyseal vessels develop from the metaphysis resulting in resorption of the physis, ossification of the mineralized cartilage of the epiphysis, and epiphyseal fusion. Although the development of the murine hip is markedly different from that in humans, we believe that these findings have direct implications for studying the vascularity of developing bone, particularly during physeal resorption, chondrocyte-mediated mineralization and more importantly, developmental diseases of the human physis and epiphysis.

► The murine proximal femoral epiphysis does not develop a secondary ossification center, but undergoes mineralization through chondrocyte dependent mechanisms. ► The murine proximal femoral physis closes after skeletal growth, a process previously thought to not occur in rodents. ► The murine proximal femoral epiphysis remains avascular during skeletal growth. ► The murine proximal femoral epiphysis develops vascularity after skeletal growth through blood vessels crossing the physis. ► Physeal closure and ossification of the proximal femoral epiphysis in mice are regulated by gender-dependent mechanisms.