QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deckelbaum, R. A. Articles by Karaplis, A. C. Search for Related Content PubMed PubMed Citation Articles by Deckelbaum, R. A. Articles by Karaplis, A. C.

Ihh enhances differentiation of CFK-2 chondrocytic cells and antagonizes PTHrP-mediated activation of PKA

¹ Department of Medicine and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada H3T 1E2
² Calcium Research Laboratory, Department of Medicine, McGill University Health Centre and McGill University, Montreal, QC, Canada H3A 1A1

^* Author for correspondence (e-mail: akarapli{at}ldi.jgh.mcgill.ca )

Accepted 23 April 2002

Indian Hedgehog (Ihh), a member of the hedgehog (HH) family of secreted morphogens, and parathyroid hormone-related peptide (PTHrP) are key regulators of cartilage cell (chondrocyte) differentiation. We have investigated, in vitro, the actions of HH signalling and its possible interplay with PTHrP using rat CFK-2 chondrocytic cells. Markers of chondrocyte differentiation [alkaline phosphatase (ALP) activity, and type II (Col2a1) and type X collagen (Col10a1) expression] were enhanced by overexpression of Ihh or its N-terminal domain (N-Ihh), effects mimicked by exogenous administration of recombinant N-terminal HH peptide. Moreover, a missense mutation mapping to the N-terminal domain of Ihh (W160G) reduces the capacity of N-Ihh to induce differentiation. Prolonged exposure of CFK-2 cells to exogenous N-Shh (5x10^-9 M) in the presence of PTHrP (10^-8 M) or forskolin (10^-7 M) resulted in perturbation of HH-mediated differentiation. In addition, overexpression of a constitutively active form of the PTHrP receptor (PTHR1 H223R) inhibited Ihh-mediated differentiation, implicating activation of protein kinase A (PKA) by PTHR1 as a probable mediator of the antagonistic effects of PTHrP. Conversely, overexpression of Ihh/N-Ihh or exogenous treatment with N-Shh led to dampening of PTHrP-mediated activation of PKA. Taken together, our data suggest that Ihh harbors the capacity to induce rather than inhibit chondrogenic differentiation, that PTHrP antagonizes HH-mediated differentiation through a PKA-dependent mechanism and that HH signalling, in turn, modulates PTHrP action through functional inhibition of signalling by PTHR1 to PKA.

Key words: Indian hedgehog, Parathyroid hormone-related peptide, Chondrocytes, Protein kinase A

This article has been cited by other articles:

				T. D. Tiet, S. Hopyan, P. Nadesan, N. Gokgoz, R. Poon, A. C. Lin, T. Yan, I. L. Andrulis, B. A. Alman, and J. S. Wunder Constitutive Hedgehog Signaling in Chondrosarcoma Up-Regulates Tumor Cell Proliferation Am. J. Pathol., January 1, 2006; 168(1): 321 - 330. [Abstract] [Full Text] [PDF]

				R. A. Deckelbaum, A. Majithia, T. Booker, J. E. Henderson, and C. A. Loomis The homeoprotein engrailed 1 has pleiotropic functions in calvarial intramembranous bone formation and remodeling Development, January 1, 2006; 133(1): 63 - 74. [Abstract] [Full Text] [PDF]

				M. Kluppel, T. N. Wight, C. Chan, A. Hinek, and J. L. Wrana Maintenance of chondroitin sulfation balance by chondroitin-4-sulfotransferase 1 is required for chondrocyte development and growth factor signaling during cartilage morphogenesis Development, September 1, 2005; 132(17): 3989 - 4003. [Abstract] [Full Text] [PDF]