Osteoblast-derived PTHrP is a physiological regulator of bone formation
T. John Martin
T. John Martin
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Commentary

Osteoblast-derived PTHrP is a physiological regulator of bone formation

Abstract

Parathyroid hormone–related protein (PTHrP) acts as a paracrine regulator in several tissues, and its physiological roles also extend to bone. In this issue of the JCI, Miao et al. demonstrate that osteoblast-specific ablation of Pthrp in mice results in osteoporosis and impaired bone formation both in vivo and ex vivo. These mice recapitulate the phenotype of mice with haploinsufficiency of Pthrp. The findings demonstrate that PTHrP plays a central role in the physiological regulation of bone formation, by promoting recruitment and survival of osteoblasts, and probably plays a role in the physiological regulation of bone resorption, by enhancing osteoclast formation. This has implications for both our understanding of the pathogenesis of osteoporosis and its treatment.

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T. John Martin

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Figure 1

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Paracrine actions of PTHrP in bone. Osteoblast progenitors in bone and b...
Paracrine actions of PTHrP in bone. Osteoblast progenitors in bone and bone marrow produce PTHrP that acts through PTHR1 on committed preosteoblasts to enhance their differentiation to mature, matrix-producing osteoblasts. The second major effect related to stimulation of bone formation is the action of PTHrP on both mature osteoblasts and osteocytes to reduce apoptosis. For PTHrP to generate an anabolic response, it needs to be presented to its targets transiently (16–18). The effect of PTHrP on the bone resorption pathway is depicted, with PTHrP acting through PTHR1 on cells of the osteoblast lineage, which respond with increased production of RANKL. This requires more prolonged stimulation by PTHrP (17, 18), and the location of these responsive cells is such that RANKL can interact with its receptor, RANK, on hemopoietic precursors to promote increased osteoclast formation and activity. In each of its local actions the potential exists for other biological activities of PTHrP to be exerted on its target cells.