Regulatory molecules, such as cytokines and growth factors, are implicated in the pathogenesis of several skeletal disorders including osteoporosis, rheumatoid arthritis and bone cancers. They modulate the activity of protein tyrosine kinases and protein tyrosine phosphatases (PTPs), enzymes controlling tyrosine phosphorylation of functional bone proteins. The precise phosphotyrosine-dependent signaling cascades by which these bone regulatory substances act have not been clearly identified, and the role of PTPs, enzymes which dephosphorylate tyrosine residues of bone proteins, is generally unknown. The applicant has discovered the first bone- and testis-specific PTP, osteotesticular PTP (OST-PTP), an enzyme which possesses structural features similar to cell adhesion molecules. OST-PTP mRNA expression is regulated during osteoblast differentiation in vitro, and is induced in osteoblasts by parathyroid hormone (PTH), an important endocrine mediator of bone remodeling. Based on these data, it is hypothesized that OST-PTP plays a crucial role in osteoblast differentiation and function. Using cell and molecular biology approaches in osteoblast-like cell lines, this hypothesis will be tested by: (1) characterizing the regulated expression of OST-PTP - (a) hormonal regulation=the intracellular signaling pathways influencing PTH-induced OST-PTP expression will be determined in UMR 106 cells and the relevant molecular mechanisms identified; and (b) differentiation-associated regulation=the influence of cell proliferation and extracellular matrix maturation on OST-PTP expression will be examined in the osteoblast-like MC3T3 cell line; (2) examining the effects of OST-PTP overexpression on osteoblast function - the effects of stable OST-PTP overexpression in MC3T3 cells on tyrosine phosphorylation of cellular proteins, cell responsivity to mitogens and PTH will be explored; and (3) examining the effects of OST-PTP overexpression on osteoblast differentiation - effects of OST-PTP overexpression on the progression of differentiation and matrix maturation in MC3T3 cells will be examined. Since the biological and clinical significance of PTP-regulated tyrosine dephosphorylation in bone tissue is currently unknown, it is suggested (by the applicant) that these proposed studies will provide valuable new information on the function of OST-PTP in osteogenesis, and the role of phosphotyrosine-linked signal transduction processes in the pathophysiology and pharmacological treatment of skeletal disorders and cancers involving bone.
|Wheeler, Marie A; Townsend, Melanie K; Yunker, Laurie A et al. (2002) Transcriptional activation of the tyrosine phosphatase gene, OST-PTP, during osteoblast differentiation. J Cell Biochem 87:363-76|
|Morrison, D F; Mauro, L J (2000) Structural characterization and chromosomal localization of the mouse cDNA and gene encoding the bone tyrosine phosphatase, mOST-PTP. Gene 257:195-208|