Smad4 Effects on Physis Morphogenesis, Chondrocyte Polarity, and Polarity Effector

Sponsor: Orthopaedic Research and Education Foundation

Location(s): United States


The physis, or growth plate, is a precisely organized structure that confers longitudinal growth through interactions of multiple signaling pathways that cooperate to control chondrocyte shape, polarity, proliferation, differentiation, and apoptosis. Mutations in Smad4, an effector of the TGF/BMP pathway, cause Myhre Syndrome, a skeletal dysplasia characterized by dwarfism and abnormal physis morphogenesis. We found smad4-deficient mice similarly exhibit physeal defects and disorganized growth plate chondrocytes. Our studies show the skeletal dysplasia resulting from Smad4 deficiency is due to disruption of chondrocyte cell shape, planar division and organelle localization, the three determinants of cellular polarity. Smad4-deficient growth plate chondrocytes have a loss of elongation in the proliferative zone with a rounded phenotype. The golgi-body distribution within the cell, a marker for cellular polarity, is cephalocaudal in the Smad4-deficient chondrocytes, in contrast with mediolateral in the wild-type. This abberant polarity in the Smad4 deficient growth plate indicates Smad4 is necessary for growth plate polarityand the TGF /BMP pathway is key in this intricate event. Current studies are examining the relationship between the Smad4 pathway and known planar cell polarity pathways in the growth