Elucidation of regulatory mechanism of osteoclast differentiation and function by extracellular calcium and phosphorus.

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Osteoclasts are the cells primarily responsible for bone resorption, and are of hematopoietic stem cell origin. In the recent decade, regulation of osteoclastic differentiation and function by many cytokines and growth factors were extensively investigated. However, our knowledge of mechanism for regulation of osteoclasts by factors other than those cytokines and growth factors is totally poor. When osteoclasts resorb mineralized bone matrix, the cells are exposed to high concentrations of ions of calcium and phosphorus such a 40 mM from bony matrics. This evidence suggests that these ions play some roles in regulating osteoclastic differentiation and function. The aim of this project is to elucidate the physiological roles of extracellular calcium and phosghorus in osteoclastic bone resorption.Osteoclasts were isolated from unfractionated rabbit bone cells, and cultured on dentine slices. Increasing concentrations of extracellular calcium, the bone-resorbing activity of the isolated o … More steoclasts decreased dose-dependently. The value of the osteoclastic bone resorption at 20 mM of extracellular calcium was about 25% of that at normal extracellular calcium (2mM) Agonists of calcium-sensing receptor (CaSR), Gd and neomycin also decreased the osteoclastic bone resorption. In similar *anner of extracellular calcium, increase in extracellular phosphorus resulted in down-regulation of osteoclastic bone-*esorbing activity. Isolated mature osteoclasts expressed CaSR, which showed a 90% homology of nucleotide sequence of parathyroid CaSR. The osteoclasts also expressed kidney-typed Na/Pi cotransporter-2.Osteoclast progenitors differentiate into mature osteoclasts in response to M-CSF and RANKL. Increase in extracellular calcium and phosphorus dose-dependently inhibited the formation of osteoclasts from bone marrow -derived macrophages. The bone marrow-derived macrophages the same types of CaSR and Na/Pi cotransporter.In conclusions, exposure of cells of osteoclast lineage to high concentrations of extracellular calcium and phosphorus decreased formation and function of osteoclasts, implying that increase in extracellular ions following bone resorption become a terminal signal of osteoclastic bone resorption. Less