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A Carboxyl-Terminal Peptide from the Parathyroid Hormone-Related Protein Inhibits Bone Resorption by Osteoclasts^*

ANNA J. FENTON, BRUCE E. KEMP, G. NEIL KENT, JANE M. MOSELEY, MING-HAO ZHENG, DOROTHY J. ROWE, JOANNE M. BRITTO, T. JOHN MARTIN and GEOFFREY C. NICHOLSON

Department of Medicine, University of Western Australia, Fremantk Hospital (A.J.F, M.-H.Z, D.J.R., J.M.B., G.C.N.) Fremantle, Western. Australia 6160;
St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne (B.E.K., J.M.M., T.J.M.) Fitzroy, Victoria 3065;
the Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital (G.N.KJ, Nedlands Western Australia 6009, Australia

Address requests for reprints to: Dr. Anna J. Fenton, Department of Medicine, University of Melbourne, Geelong Hospital, Geelong, Victoria 3220, Australia.

Abstract

PTH-related protein (PTHrP) interacts, via its amino-terminal 34 residues, with PTH receptors on osteoblasts to stimulate osteoclastic bone resorption indirectly. We now report that mature hPTHrP-f 1-141) (EC₅₀, -l0^-11 M) and a carboxyl-terminal fragment, PTHrP-(107–139) (EC₅₀, -10^-15 M), are potent inhibitors of resorption in an isolated rat osteoclast bone resorption assay, whereas hPTHrP-(l–108) and hPTHrP-(1–34) are inactive in this respect. PTHrP-(107–139) also inhibits resorption in a rat long bone organ culture system and reduces osteoclast spreading. PTHrP-(107–139) does not act on osteoclasts via a cAMP signal transduction mechanism, but its effects may be mediated by protein kinase-C. This previously unrecognized action of PTHrP, to inhibit osteoclastic bone resorption directly, indicates that PTHrP may be a precursor of multiple biologically active peptides with differing physiological functions. (Endocrinology 129: 1762–1768, 1991)

Footnotes

^* This work was supported by grants from the University of Western Australia, the Anti-Cancer Council of Victoria, and the National Health and Medical Council of Australia.

Recipient of an Eric Cyril Lawrence Medical Research Fellowship.

Received May 17, 1991.

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