Osteoporosis is a major bone disorder that affects both men and women during aging. The pathogenesis is not only due to the increased osteoclast activity in bone resorption, but also a decrease in bone formation mostly attributed to an insufficient supply of osteoblasts in the aged. Parathyroid hormone (PTH) regulates calcium homeostasis and bone metabolism, and plays an important role in coupling of bone resorption and bone formation. Thus, regulation of PTH signaling could be a solution for osteoporosis and other degenerative bone disorders. A serine/threonine kinase receptor kinase, TGF2 type II receptor (T2RII), was found to interact with PTH receptor (PTH1R) and phosphorylate cytoplasmic domain of PTH1R. We reason that this kinase-substrate reaction coordinates PTH and TGF2 signaling and drives anabolic effect of PTH on bone. Thus, a series of experiments and animal models are designed to confirm the hypothesis that phosphorylation of PTH1R by T2RII integrates signaling of bone remodeling.
Specific Aims to accomplish this are:
Specific Aim 1 : Determine the function of targeted phosphorylation of PTH1R by T2RII in PTH and TGF2 signaling. 1a. Determine the T2RII-targeted phosphorylation sites on PTH1R and generate antibodies against phosphorylated PTH1R. 1b. Examine the effect of PTH1R phosphorylation by T2RII on PTH and TGF2 signaling.
Specific Aim 2 : Determine the role of targeted phosphorylation of PTH1R by T2RII in bone remodeling. 2a. Characterize the role of PTH/cAMP signaling and TGF2/Smad signaling in bone phenotype of T2RII knockout mice. 2b. Examine the effect of PTH1R deletion on TGF2 function in bone remodeling. 2c. Examine the effect of transgenic expression of a small T2RII substrate on bone remodeling. This proposal may reveal a previously unrecognized function for T2RII in bone remodeling and a mechanism for PTH to regulate local growth factor at the level of membrane receptor.
We propose a study to elucidate mechanisms of parathyroid hormone (PTH) in regulation of local growth factors in bone. The work will provide new perspectives and knowledge into treatment of bone disorders including osteoporosis.