The objective of the proposed research is to understand the role of Bone Morphogenic Protein 2 (BMP2) in the postnatal growth, pathogenesis and adaptive remodeling of mandibular condylar cartilage (MCC). The long- term goal of the applicant (PI) is to understand the mechanism regulating the growth and differentiation of MCC. Temporomandibular joint disorders (TMDs) affect over 15 million Americans and it is estimated that the United States spends billions of dollars each year on TMDs. Bone Morphogenic Proteins (BMPs) signaling is crucial for the development and postnatal maintenance of MCC, while overexpression of BMP signaling has been associated with degenerative disorders of the cartilage. Despite a wealth of literature on BMPs signaling in articular cartilage of the knee, little is known about BMPs role in postnatal growth, adaptive remodeling and pathogenesis of MCC. In our MCC loading model we found increased cartilage thickness, increased matrix synthesis and mineralization, as well as increased hypertrophic differentiation of chondrocytes. Moreover, conditional deletion of BMP2 in MCC showed decreased synthesis and mineralization of extracellular matrix and decreased hypertrophic differentiation of chondrocytes. These data suggest that BMP2 regulates MCC growth and differentiation. However, the mechanisms underlying the regulatory effects of BMP2 in the matrix synthesis and hypertrophic differentiation of chondrocytes in MCC remain unknown. Our global hypothesis is that BMP2 is required for postnatal growth and adaptive remodeling of the MCC. Our understanding is that BMP2 is the master regulator of extracellular matrix synthesis, matrix mineralization and hypertrophic differentiation of chondrocytes. To test this hypothesis, we propose the following specific aims:
Specific Aim 1 : To determine the effects and mechanism of BMP2 loss of function on MCC and the subchondral bone. Using a transgenic mice model with lineage specific deletion of BMP2, we will examine the outcomes of BMP2-loss-of-function on MCC and the subchondral bone.
Specific Aim 2 : To determine if the anabolic effect of TMJ loading in young mice is mediated through BMP2 signaling. We will utilize two complementary in vivo mice loading/unloading models, which causes either an increase or decrease in extracellular matrix mineralization and hypertrophic differentiation of chondrocytes.
Specific Aim 3 : The effect of BMP2 loss of function on the Ihh signaling pathway. Using specific activators and inhibitors in an ex vivo organ culture model we will investigate possible cross-talk between BMP2 and Ihh signaling in regulating anabolic response in MCC. Greater understanding of the effect of BMP2 loss-of-function on the postnatal growth and pathogenesis of MCC will aid in the understanding of the diseases of the TMJ and will help us in translating new approaches to regenerate the joint.
The temporomandibular joint disorders (TMDs) affect over 15 million Americans and it is estimated that US spends billions of dollars each year on TMDs. Bone Morphogenic Proteins (BMPs) signaling is crucial for the postnatal maintenance of Mandibular Condylar Cartilage (MCC). Contradictorily, overexpression of BMP signaling has been associated with degeneration of MCC. This proposal aims to understand the mechanism and the role of BMP2 in postnatal growth and adaptive remodeling of MCC. Greater knowledge on how MCC growth and remodeling is effected by the loss of BMP2 will aid in the understanding the disease of MCC and will help us in translating new approaches to regenerate joint.
