Birth and Death of Bone Cells: Basic Regulatory Mechanisms and Implications for the Pathogenesis and Treatment of Osteoporosis*

Abstract

The adult skeleton regenerates by temporary cellular structures that comprise teams of juxtaposed osteoclasts and osteoblasts and replace periodically old bone with new. A considerable body of evidence accumulated during the last decade has shown that the rate of genesis of these two highly specialized cell types, as well as the prevalence of their apoptosis, is essential for the maintenance of bone homeostasis; and that common metabolic bone disorders such as osteoporosis result largely from a derangement in the birth or death of these cells. The purpose of this article is 3-fold: 1) to review the role and the molecular mechanism of action of regulatory molecules, such as cytokines and hormones, in osteoclast and osteoblast birth and apoptosis; 2) to review the evidence for the contribution of changes in bone cell birth or death to the pathogenesis of the most common forms of osteoporosis; and 3) to highlight the implications of bone cell birth and death for a better understanding of the mechanism of action and efficacy of present and future pharmacotherapeutic agents for osteoporosis.

Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation

“…PGE 2 -EP4 appears to induce both osteoblastogenesis and osteoclastogenesis and to integrate the two actions temporarily and spatially in situ in bone remodeling. In this respect, the action of PGE 2 may be similar to that of PTH, which also promotes both bone formation and resorption (1,3,22). Recently, clinical efficacy of PTH for postmenopausal osteoporosis has been reported (23).…”

“…B ones undergo continuous remodeling through repeated cycles of destruction and rebuilding (1). This remodeling is mediated by the well balanced actions of osteoclasts, which resorb old bones, and osteoblasts, which form new bones.…”

Oligogalacturonic acid inhibit bone resorption and collagen degradation through its interaction with type I collagen

“…The resulting acidification dissolves the mineral part of the bone, exposing the collagenous matrix to both lysosomal cysteine proteases such as Cathepsin K and matrix metalloproteinases such as MMP-9 (5-7) secreted by mature osteoclasts. At the end of the bone resorption process, osteoclasts die through an apoptotic cell death (8).…”

Anti-apoptotic Molecule Bcl-2 Regulates the Differentiation, Activation, and Survival of Both Osteoblasts and Osteoclasts

“…The majority of osteoblasts that are assembled at the remodeling site also die by apoptosis. The remaining osteoblasts are converted to lining cells that cover quiescent bone surfaces or are embedded within the mineralized matrix as osteocytes (4). Several studies have revealed that the apoptosis of osteoblasts and osteoclasts is strictly regulated and plays important roles in maintaining skeletal integrity (5)(6)(7)(8).…”