UCLA

Endochondral ossification involves a highly coordinated program of chondrocyte differentiation, proliferation, maturation, and hypertrophy. The bone morphogenetic protein (BMP) and transforming growth factor beta (TGFβ)/activin pathways are important regulators of these processes. The importance of extracellular antagonists as regulators of the duration, intensity and extent of BMP and TGFβ/activin signaling has been defined. For example, mice lacking the BMP receptor antagonist Noggin exhibit cartilage overgrowth concurrent with excessBMP activity. However, very little is known about the roles of intracellular inhibitors of BMP and TGFβ/activin pathways, such as the inhibitory Smad (I-Smad) proteins, Smad6 and Smad7. In vitro studies reveal that I-Smads 6 and 7 can regulate BMP- and TGFβ-mediated effects on chondrocytes. Although in vivo studies in which I-Smads were overexpressed in cartilage have shown that I-Smads have the potential to limit BMP signaling in vivo, the physiological relevance of I-Smad activity in skeletal tissues remains unknown. Furthermore, whether I-Smads impact TGFβ signaling in cartilage during development is unclear.

This thesis includes two reviews (both have been published) and two original articles (one of which has been published). First, the known mechanisms by which BMP signaling regulate chondrogenesis, osteogenesis, and adipogenesis will be highlighted Chapter One, "BMP signaling in Skeletogenesis." Then, the roles of Smad proteins, which are the mediators of the canonical BMP/TGFβ pathways, in regulating skeletal development will be highlighted in Chapter Two, "Smad signaling in skeletal development and regeneration." Finally, the roles of Smad6 and Smad7 in endochondral bone formation will be described in Chapters Three ("Smad6 is essential to limit BMP signaling in cartilage development") and Four ("Smad7 regulates terminal maturation of chondrocytes during cartilage development in mice"). The last chapter will discuss the overall conclusions and future directions of my thesis project.