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

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)