The integral role of fibronectin in skeletal morphogenesis and pathogenesis

Fibronectin (FN) serves as a critical organizer of extracellular matrix networks in two principal isoforms, the plasma FN and the cellular FN. While FN's pivotal role in various organ systems, including the blood vasculature, is well-established, its contribution to the development of the skeletal system is much less explored. Furthermore, the pathomechanisms of spondyloepiphyseal dysplasia caused by FN mutations remain elusive. In this minireview, we discuss findings from our recent two studies using i) an iPSC-based cell culture model to explore how FN mutations in spondyloepiphyseal dysplasia impact mesenchymal cell differentiation into chondrocytes and ii) conditional FN knockout mouse models to determine the physiological roles of FN isoforms during postnatal skeletal development. The data revealed that FN mutations cause severe intracellular and matrix defects in mesenchymal cells and impair their ability to differentiate into chondrocytes. The findings further demonstrate the important roles of both FN isoforms in orchestrating regulated chondrogenesis during skeletal development. We critically discuss the findings in the context of the existing literature.