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

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-(1-141) (EC50, approximately 10(-11) M) and a carboxyl-terminal fragment, PTHrP-(107-139) (EC50, approximately 10(-15) M), are potent inhibitors of resorption in an isolated rat osteoclast bone resorption assay, whereas hPTHrP-(1-108) 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.

Parathyroid hormone-related protein (107-111) improves the bone regeneration potential of gelatin–glutaraldehyde biopolymer-coated hydroxyapatite

“…This was not surprising, considering the ability of this peptide to reduce the number of trabecular osteoclasts when administered subcutaneously, as recently reported [45], and the observed increase in OPG/RANKL mRNA ratio induced by PTHrP (107-111)-loaded HA Glu scaffolds in osteoblast cultures in this work. In fact, PTHrP (107-139) has consistently been shown to display anti-resorptive features in rodents [17,[20][21][22], apparently by interacting with osteoclasts directly or indirectly through targeting osteoblasts [19,23,26,28]. Also in this regard, the local presence of PTHrP (107-111) was shown to inhibit the transient inflammatory response as well as the appearance of osteoclasts in a cavitary bone defect in the rabbit femur [27].…”

“…By using this method, the mean uptake of PTHrP (107-111) by these scaffolds after 24 h of loading was 60%, equivalent to 0.7 ng of peptide per mg of scaffold. Meanwhile, 80% of this amount was released to the surrounding medium within 1 h, and virtually 100% at 48 h. It was previously shown that minor amounts of this peptide (in the sub-nanomolar range) still sustained biological activity [18,23,25,26].…”

“…An emerging factor in this regard is parathyroid hormone-related protein (PTHrP), the N-terminal fragment of which has been shown to induce bone anabolic actions in rodents and humans upon systemic daily administration [15,16]. In addition, the C-terminal 107-111 domain (also known as osteostatin) of PTHrP also exhibits osteogenic features in vitro, and stimulates bone accrual in vivo [17][18][19][20][21][22][23][24][25]. Of note, we recently showed that loading non-degradable Si-based ceramics with the latter pentapeptide gives them osteogenic and angiogenic features both in vitro and in vivo as implants in a cavitary defect in the rabbit femur [26][27][28][29].…”

Synthesis of human parathyroid‐hormone‐related protein(1–141) in Saccharomyces cerevisiae

“…Recently, distinct actions of different regions of PTHrP have been discovered; in addition to the ability of the Nterminal region to activate adenylate cyclase, an effect on placental calcium transport has been located to a mid-region fragment of PTHrP [8], while inhibition of osteoclast bone resorption is mediated by a C-terminal fragment of the protein [9]. Several regions representing putative proteolytic processing sites are present throughout the PTHrP amino acid sequence [4], and both mid-region and carboxyl-terminal fragments have been found as possible circulating forms [25,261.…”

Parathyroid Hormone–Related Protein as a Regulator of pRb and the Cell Cycle in Arterial Smooth Muscle

“…The 107-111 region was selected for deletion because it is extremely highly conserved among mammalian species, in contrast to the 112-139 region, which is less well conserved. [3][4][5][21][22][23][24][25] The other regions (112-120, 121-130, and 131-139) were selected randomly for deletion, because there is no known functional significance of these segments. Surprisingly, as shown in Figure 2B, despite its intense evolutionary conservation, deletion of the 107-111 region had no adverse effect on proliferation.…”