Theses Doctoral

Non-autonomous regulation of bone mass accrual and the role of T-cell protein tyrosine phosphatase in the bone regulation of insulin sensitivity

Zee, Tiffany

The skeleton is a highly dynamic organ that undergoes constant remodeling to renew itself and maintain bone mass. It is subject to regulation from both hormones produced in peripheral tissues and neuronal control by the nervous system. Recent studies have shown that the skeleton is also an endocrine organ, releasing the hormone osteocalcin that increases insulin secretion and sensitivity in the pancreas and testosterone production in the Leydig cells of the testis. In my thesis study, I explore both the cell-nonautonomous regulation of osteoblast differentiation and the bone regulation of energy metabolism using cell-specific gene inactivation in the mouse. Early B-cell factor 1 (Ebf1) is a transcription factor whose inactivation in all cells results in high bone mass because of an increase in bone formation. To test if Ebf1 regulates bone formation cell-autonomously, I analyzed pattern of expression and its function in osteoblasts. I show here that in vivo deletion of in osteoblast progenitors does not affect osteoblast differentiation or bone formation accrual post-natally, indicating that the phenotype described in Ebf1 mice is not osteoblast-autonomous. Insulin signaling in osteoblasts contributes to whole body glucose homeostasis in the mouse and in humans by increasing the activity of osteocalcin. The osteoblast insulin signaling cascade is negatively regulated by ESP, a tyrosine phosphatase dephosphorylating the insulin receptor. is one of many tyrosine phosphatases expressed in osteoblasts, and this observation suggests that other protein tyrosine phosphatases may contribute to the attenuation of insulin receptor phosphorylation in this cell type. In this study, we sought to identify additional PTP(s) that like ESP, would function in the osteoblast to regulate insulin signaling and thus affect activity of the insulin-sensitizing hormone osteocalcin. For that purpose, we used as criteria, expression in osteoblasts, regulation by isoproterenol, and ability to trap the insulin receptor in a substrate-trapping assay. Here we show that the T-cell protein tyrosine phosphatase (TC-PTP) regulates insulin receptor phosphorylation in the osteoblast, thus compromising bone resorption and bioactivity of osteocalcin. Accordingly, osteoblast-specific deletion of TC-PTP (Ptpn2) promotes insulin sensitivity in an osteocalcin-dependent manner. This study increases the number of genes involved in the bone regulation of glucose homeostasis.


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More About This Work

Academic Units
Genetics and Development
Thesis Advisors
Karsenty, Gerard
Ph.D., Columbia University
Published Here
January 28, 2013