This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goomer, R. S. Articles by Terkeltaub, R. Search for Related Content PubMed PubMed Citation Articles by Goomer, R. S. Articles by Terkeltaub, R.

The Tetrabasic KKKK^147–150 Motif Determines Intracrine Regulatory Effects of PTHrP 1–173 on Chondrocyte PPi Metabolism and Matrix Synthesis¹

Department of Orthopedics (R.S.G., D.A., T.M.M.), University of California, San Diego School of Medicine, La Jolla, California 92093-0630; and Department of Medicine (K.A.J., D.W.B., A.G., L.J.D., R.T.), Veterans Affairs Medical Center, University of California, San Diego School of Medicine, San Diego, California 92161

Address all correspondence and requests for reprints to: L. J. Deftos, M.D., VAMC, 3350 La Jolla Village Drive, San Diego, California 92161. E-mail: ljdeftos{at}ucsd.edu

Expression of PTHrP is a major regulator of growth cartilage development and also becomes robust in osteoarthritic cartilage. We further defined how PTHrP 1–173, which we observed to be the preferentially expressed PTHrP isoform in normal and osteoarthritic cartilage, functions in chondrocytes. We transfected both immortalized human juvenile costal chondrocytes (TC28 cells) and rabbit articular chondrocytes with wild-type PTHrP 1–173 and mutants of putative PTHrP 1–173 endoproteolytic processing sites. Wild-type PTHrP 1–173 inhibited collagen synthesis and decreased extracellular PPi (which critically regulates hydroxyapatite deposition) by 50–80% in both chondrocytic cell types. In contrast, PTHrP 1–173 mutated at the PTHrP 147–150 motif KKKK (but not the other site-directed mutants) and increased both extracellular PPi and collagen synthesis by >50%. Synthetic PTHrP 140–173 mutated at amino acids 147–150 and also increased extracellular PPi, and wild-type 140–173 decreased extracellular PPi in permeabilized cells. The 147–150 KKKK domain of PTHrP 1–173 acted, in part, by regulating nuclear localization of PTHrP. We conclude that the tetrabasic 147–150 motif functions to determine how PTHrP 1–173 regulates collagen synthesis and levels of extracellular PPi by an intracrine mechanism in chondrocytes, and it may prove useful as a therapeutic target for regulation of mineralization.

This article has been cited by other articles:

				J. J. Grzesiak, K. C. Smith, C. Chalberg, C. Truong, D. W. Burton, L. J. Deftos, and M. Bouvet Heat Shock Protein-70 Expressed on the Surface of Cancer Cells Binds Parathyroid Hormone-Related Protein in Vitro Endocrinology, August 1, 2005; 146(8): 3567 - 3576. [Abstract] [Full Text] [PDF]

				R. H. Hastings, F. Araiza, D. W. Burton, M. Bedley, and L. J. Deftos Parathyroid hormone-related protein regulates apoptosis in lung cancer cells through protein kinase A Am J Physiol Cell Physiol, December 1, 2004; 287(6): C1616 - C1622. [Abstract] [Full Text] [PDF]

				R. H. Hastings, F. Araiza, D. W. Burton, L. Zhang, M. Bedley, and L. J. Deftos Parathyroid hormone-related protein ameliorates death receptor-mediated apoptosis in lung cancer cells Am J Physiol Cell Physiol, December 1, 2003; 285(6): C1429 - C1436. [Abstract] [Full Text] [PDF]

				R. H. Hastings, R. A. Quintana, R. Sandoval, D. W. Burton, and L. J. Deftos Amino-terminal and midmolecule parathyroid hormone-related protein, phosphatidylcholine, and type II cell proliferation in silica-injured lung Am J Physiol Lung Cell Mol Physiol, December 1, 2003; 285(6): L1312 - L1322. [Abstract] [Full Text] [PDF]

				R. H. Hastings, A. Asirvatham, R. Quintana, R. Sandoval, R. Dutta, D. W. Burton, and L. J. Deftos Parathyroid hormone-related protein-(38-64) regulates lung cell proliferation after silica injury Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L12 - L21. [Abstract] [Full Text] [PDF]

				R. Liu, K. Aupperle, and R. Terkeltaub Src family protein tyrosine kinase signaling mediates monosodium urate crystal-induced IL-8 expression by monocytic THP-1 cells J. Leukoc. Biol., December 1, 2001; 70(6): 961 - 968. [Abstract] [Full Text] [PDF]

				R. A. Terkeltaub Inorganic pyrophosphate generation and disposition in pathophysiology Am J Physiol Cell Physiol, July 1, 2001; 281(1): C1 - C11. [Abstract] [Full Text] [PDF]

				K. Johnson, S. Hashimoto, M. Lotz, K. Pritzker, and R. Terkeltaub Interleukin-1 Induces Pro-Mineralizing Activity of Cartilage Tissue Transglutaminase and Factor XIIIa Am. J. Pathol., July 1, 2001; 159(1): 149 - 163. [Abstract] [Full Text] [PDF]