BoneKEy-Osteovision | Commentary
Mineral ions and osteoblast apoptosis
DOI:10.1138/2001039
The process of programmed cell death (apoptosis) serves several crucial biological functions. It provides a means of eliminating cells that acquire chromosomal damage or have dysregulated cell cycles, thus preventing possible malignant progression. Apoptotic cell death is also common in developing tissues where it is an essential component of tissue and organ morphogenesis. Apoptosis is also a common process in the immune system and in developed tissues where it serves to control the number and distribution of cells with particular phenotypic properties.
Apoptosis is thought to play an important role in regulating skeletal development and function. Terminally differentiated chondrocytes undergo apoptosis and replacement by osteogenic cells during the course of endochondral bone formation (). During bone remodeling, apoptosis of osteoclasts limits the lifespan of these cells (). Factors such as mCSF and RANK ligand that promote osteoclastogenesis also serve to inhibit the apoptosis of mature osteoclasts, whereas the anti-resorptive agents calcitonin and bisphosphonates are pro-apoptotic (). Relatively less is known about the control of apoptosis in cells of the osteoblast lineage. In vivo studies have demonstrated that osteoblasts and osteocytes undergo apoptosis relatively frequently in developing bone, but rarely in mature bone (). When apoptosis does occur, it is mostly found at sites of active bone remodeling.
Little is known about the factors that control osteoblast apoptosis or the physiological importance of this process. Manolagas and coworkers have demonstrated that in vivo administration of PTH reduces the frequency of osteoblast apoptosis, and suggest that this could account for much of the anabolic response of the skeleton to exogenous PTH (). A variety of growth factors as well as PTH have been shown to inhibit the apoptosis of osteoblasts in vitro (). On the other hand, glucocorticoids and TNFα enhance osteoblast apoptosis at least in vitro. These are potentially important results, but they leave open the question of whether normal physiological signals serve to regulate the lifespan of the osteoblast.
Recent findings raise the possibility that the solubilization of bone mineral occurring during the course of normal bone remodeling serves as a stimulus to osteoblast apoptosis. Meleti et al. () have reported that phosphate ions are sufficient to induce the apoptosis of human osteoblasts in secondary culture. This effect was progressive as cells were exposed to increasing concentrations of phosphate (from 1 to 7 mM), and apoptosis was blocked by phosphonoformic acid, an inhibitor of plasma membrane Na-phosphate transporters. This same group had reported similar apoptotic effects of phosphate in cultured chondrocytes (), although the latter cells were more sensitive to phosphate than are human osteoblasts.
More recently, Adams et al. () have reported that extracellular calcium (Ca2+) sensitizes osteoblasts to the apoptotic action of phosphate. Acute exposure of human osteoblasts (and MC3T3-E1 cells) to increasing levels of Ca2+ (from 1.8 to 2.9 mM) increased apoptosis at levels of extracellular phosphate between 3 and 7 mM. Loss of cell viability was evident within 2 to 6 hours of exposure of cells to calcium and phosphate. This appears to represent true apoptosis, as evidenced by TUNEL assay, caspase activation, and changes in mitochondrial membrane potential as well as cell morphology. How extracellular calcium and phosphate promote osteoblast apoptosis is not clear. Even at high extracellular calcium, phosphate-induced apoptosis is blocked by phosphonoformic acid. Thus, phosphate entry is requisite for apoptosis. The potentiating action of calcium on the other hand persists in the presence of the voltage-dependent calcium channel blocker verapamil, although the non-specific calcium channel blocker lanthanum has a weak protective effect. The data suggest that classical pathways for cellular calcium entry are not required for the apoptotic response.
These studies raise some important questions concerning the potential role of calcium and phosphate in controlling osteoblast survival. What is the precise mechanism underlying the apoptotic action of calcium and phosphate? The authors suggest that microparticles of calcium phosphate may cluster at the cell surface and trigger apoptosis. But that would not readily explain the need for phosphate uptake through Na-phosphate transporters in the apoptotic response. Perhaps the potentiating effect of Ca2+ involves the activation of calcium-sensing receptors which have been identified in osteoblastic cells (). This would lead to activation of intracellular signaling pathways (such as increased cytosolic calcium) capable of promoting apoptosis in other cell types (). What is the role of cell-matrix attachment in the apoptotic response to calcium and phosphate? Most importantly, what is the functional significance of the apoptotic response of osteoblasts to calcium and phosphate? Release of mineral ions as a consequence of bone resorption on active bone remodeling surfaces could produce apoptosis of nearby osteoblasts. If so, this process could have a major impact on the balance between bone formation and resorption during the remodeling process. Clearly, further studies are warranted to define the role and mechanism underlying the apoptotic effects of calcium and phosphate on osteoblasts.
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