Cell Biological Investigation of Disturbances in Bone Cell Functions with their Application to the Treatment of Osteoporosis

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In order to clarify the underlying mechanism for the development of osteoporosis, as well as to search for the ways to prevent and treat osteoporosis, the following investigations were performed :1. Bone resorption-stimulating activity(BRSA) elaborated form osteoblasts under stimulation by calciotropic hormones : Treatment of osteoblastic cells with 1,25(OH)_2D stimulated the elaboration of BRSA.The factor(s) were associated with cell-matrix surface and showed an affinity for heparin. The BRSA was purified by reversed phase HPLC and gel filtration chromatography to obtain two peaks. Further purification is under way to identify this factor.2. Bone resorption-inhibitory activity(BRIA) elaborated from osteoblasts under stimulation by estrogen : Treatment of osteoblastic cells with estrogen caused the elaboration of BRIA.The BRIA was also associated with cell/matrix surface and exhibited affinity for heparin. The factor was inactivated by heat and trypsin treatment, suggesting that it was a protein.3. Regulation of osteoclast formation and function : Osteoclastic bone resorption was inhibited by 24,25(OH)_2D.Because 24,25(OH)_2D inhibited both the formation of osteoclastic cells from hemopoietic stem cells and the resorption pit formation by rabbit osteoclasts on dentine slices, it appeared to inhibit both the formation and function of osteoclasts. The effect of extracellular Ca on oeteoclast membrane inward rectifying K channel was also investigated. It was found that the elevation in extracellular Ca enhanced depolarization of osteoclasts by inhibiting the inward rectifying K channel.4. Regulation of the production and actions of growth factors in osteoblasts : Long-term cultures of osteoblastic cells enhance the differentiation. The differentiation of osteoblasts was associated with a loss of both types I and II TGF-beta receptors and the effect of TGF-beta on these cells.