Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone
Robert L. Jilka, … , A. Michael Parfitt, Stavros C. Manolagas
Robert L. Jilka, … , A. Michael Parfitt, Stavros C. Manolagas
Published August 15, 1999
Citation Information: J Clin Invest. 1999;104(4):439-446. https://doi.org/10.1172/JCI6610.
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Article

Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone

Abstract

The mass of regenerating tissues, such as bone, is critically dependent on the number of executive cells, which in turn is determined by the rate of replication of progenitors and the life-span of mature cells, reflecting the timing of death by apoptosis. Bone mass can be increased by intermittent parathyroid hormone (PTH) administration, but the mechanism of this phenomenon has remained unknown. We report that daily PTH injections in mice with either normal bone mass or osteopenia due to defective osteoblastogenesis increased bone formation without affecting the generation of new osteoblasts. Instead, PTH increased the life-span of mature osteoblasts by preventing their apoptosis — the fate of the majority of these cells under normal conditions. The antiapoptotic effect of PTH was sufficient to account for the increase in bone mass, and was confirmed in vitro using rodent and human osteoblasts and osteocytes. This evidence provides proof of the basic principle that the work performed by a cell population can be increased by suppression of apoptosis. Moreover, it suggests novel pharmacotherapeutic strategies for osteoporosis and, perhaps, other pathologic conditions in which tissue mass diminution has compromised functional integrity.

Authors

Robert L. Jilka, Robert S. Weinstein, Teresita Bellido, Paula Roberson, A. Michael Parfitt, Stavros C. Manolagas

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Mechanism and signal specificity of the suppressive effect of PTH on apo...
Mechanism and signal specificity of the suppressive effect of PTH on apoptosis in cultures of osteoblastic and osteocytic cells. (a) Cultures were maintained for 6 hours in the presence of 10–7 M dexamethasone (Dex) without or with preincubation for 1 hour with 10–8 M bPTH(1-34). The pyknotic fragmented nuclei (arrows) typical of apoptotic cells were viewed using HOECHST 33258 fluorescent dye in osteoblastic calvaria cells and by EGFP fluorescence in MLO-Y4 osteocytes. ×400. Insets: percentage of cells undergoing apoptosis, as determined from evaluation of nuclear morphology of 500 cells in randomly selected fields. (b) Cells (104/cm2) were incubated for 1 hour in vehicle or 10–8 M bPTH(1-34), and then incubated for an additional 6 hours in the absence (basal) or presence of 5 × 10–5 M etoposide (Etop), 10–7 M dexamethasone (Dex), or 10–9 M TNF. (c) Osteoblastic calvaria cells were cultured for 1 hour in vehicle or the indicated log molar concentrations of bPTH(1-34), bPTH(3-34), or dibutyryl cAMP (DB-cAMP), and then for an additional 6 hours in the absence or presence of 10–7 M dexamethasone. Apoptotic cells in b and c were enumerated by trypan blue staining. Bars represent mean ± SD of triplicate wells. Nearly identical results were obtained in at least 2 additional experiments. Data were analyzed by ANOVA. Etoposide, dexamethasone, and TNF caused a significant (P < 0.05) increase in apoptosis in cultures containing vehicle. *P < 0.05 vs. vehicle (b) or vs. dexamethasone alone (c).