Bone biology osteoclasts

Roodman GD (1996) Advances in bone biology the osteoclast Endocr Rev 17 308-332... 

Contrary to the original assumption which linked the inhibition of bone resorption solely to physico-chemical adsorption of the BP onto the bone surface, there is new evidence indicating cellular mechanisms of BP action, although a prerequisite of the biological activity is still the adsorption. The bisphosphonates deposited on the bone surface poison the bone-resorbing osteoclasts after being internalized by them. 

The steroid hormone 1,25-dihydroxy vitamin D3 (calcitriol) slowly increases both intestinal calcium absorption and bone resorption, and is also stimulated through low calcium levels. In contrast, calcitonin rapidly inhibits osteoclast activity and thus decreases serum calcium levels. Calcitonin is secreted by the clear cells of the thyroid and inhibits osteoclast activity by increasing the intracellular cyclic AMP content via binding to a specific cell surface receptor, thus causing a contraction of the resorbing cell membrane. The biological relevance of calcitonin in human calcium homeostasis is not well established. 

Bisphosphonates bind to hydroxyapatite in bone and decrease resorption by inhibiting osteoclast adherence to bone surfaces. All bisphosphonates become incorporated into bone, giving them long biologic half-lives of up to 10 years. 

The adult skeleton is periodically remodeled by transitory anatomic structures that contain juxtaposed osteoclast and osteoblast teams and that replace old bone with new bone. The purpose of this remodeling is both to prevent bone aging and repair the damage that occurs as well as to guarantee a contribution of minerals, especially calcium, to body cells for their correct function. In the last few years, due mainly to the research in molecular biology and cellular differentiation and to studies of genetically manipulated mice, it has been possible to discover many aspects both of the cellular and molecular bases of this bone remodeling as well as of the differentiation and function of the two main implied cell types osteoblasts and osteoclasts. 

If the RANKL/OPG system is a final effector on the biology of osteoclasts, then this system should be the basis for the antiresorptive effects of estrogen. Indeed, estrogen stimulates OPG synthesis for osteoblastic cells (Hofbauer et al. 1999), estrogen deficiency induced by OVX results in a decrease in OPG and increased RANKL production, an action that is prevented by estradiol administration, and OPG administration prevents bone loss induced by OVX (Simonet et al. 1997 Hofbauer et al. 2000 Hofbauer 1999). In addition, estrogen can suppress RANKL and M-CSF-induced differentiation of myelomonocytic precursors into multinucleated TRAP+ osteoclasts through an ER-dependent mechanism that does not require mediation by stromal cells (Shevde et al. 2000). Finally, treatment with estradiol inhibits the response of osteoclast precursors to the action of RANKL (Srivastava et al. 2001). 

Hofbauer LC (1999) Osteoprotegerin ligand and osteoprotegerin novel implications for osteoclast biology and bone metabolism. Eur J Endocrinol 141 195-210... 

Pavlov, N.J., Xu, J., Riedel, D., Yeoh, J.S., Teitelbaum, S.E., Papadimitriou, J.M., Jahn, R., Ross, F.P., and Zheng, M.H. (2005) Rab3D Regulates a Novel Vesicular Trafficking Pathway That Is Required for Osteoclastic Bone Resorption. Molecular Cell Biology li, 5253-5269. 

Three hormones serve as the principal regulators of calcium and phosphate homeostasis parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and the steroid vitamin D (Figure 42-2). Vitamin D is a prohormone rather than a true hormone, because it must be further metabolized to gain biologic activity. PTH stimulates the production of the active metabolite of vitamin D, l,25(OH)2D. l,25(OH)2D, on the other hand, suppresses the production of PTH. l,25(OH)2D stimulates the intestinal absorption of calcium and phosphate. l,25(OH)2D and PTH promote both bone formation and resorption in part by stimulating the proliferation and differentiation of osteoblasts and osteoclasts. Both... 

Sun L, Adebanjo OA, Moonga BS, Corisdeo S, Anandatheerthavarada HK, Biswas G, Arakawa T, Hakeda Y, Koval A, Sodam B, Bevis PJ, Moser AJ, Lai FA, Epstein S, Troen BR, Kumegawa M, Zaidi M. 1999. CD38/ADP-ribosyl cyclase a new role in the regulation of osteoclastic bone resorption. J Cell Biology 146 1161-71. 

The benzothiophene derivative raloxifene (Evista /Lilly) is a selective estrogen receptor modulator (SERM). Raloxifene produces its biological actions via modulation (both activation and blockade) of estrogen receptors that ultimately results in decreased resorption of bone. The bisphosphonate derivative alendronate (Fosamax /Merck), an inhibitor of osteoclast-mediated bone resorption, is also useful in the treatment of osteoporosis. Both raloxifene and alendronate are useful in the treatment of osteoporosis in postmenopausal women. 

Fig. 10.1 Osteoclasts tunneling. Osteoclasts differentiate at cracks in the bone and form a tunnel (lacuna) containing a central capillary surrounded by connective tissue. Fibroblast-like precursors of osteoblasts are activated to become osteoblasts and new bone is formed (Modified from Fig. 22.54 in The Molecular Biology of the Cell. B. Alberts et al., 4th Ed. 2002. Garland Science, Taylor Francis Group, New York)...

Calcium ions are mostly present in bones or chelated to biological molecules. In blood plasma, only 1% of the calcium ions present are unbound 78% is bound to albumin, 8% to citrate, and 13% to other plasma proteins. The free calcium ions are prevented from precipitating by plasma pyrophosphate. Calcium ions are also stored in the endoplasmic reticulum (ER), mostly chelated to ER-resident proteins and phosphatidylser-ine. Free calcium ions may be released through transient receptor potential channels to the cytosol where it activates numerous physiological processes. If the free calcium ion concentration of blood plasma falls, parathyroid hormone (PTH) is secreted by the parathyroid gland cells. PTH speeds up the transport of demineralized bone products by osteoclasts. In the kidney, it increases the excretion of phosphate and decreases the excretion of calcium. PTH also acts on kidney cells to make calcitriol from vitamin D, which induces calcium transporters in the intestine and osteoclasts. PTH mediates these effects by activating G-protein-coupled receptors in the kidney and osteoclasts. 

Hydroxylapatite in the sintered form is less soluble than biologically formed HAp in bone and teeth, attributable to the fine crystal size and substituent elements. The solubility of sintered hydroxylapatite is increased with additions of strontium (Christoffersen et al. 1997, Okayama et al. 1991) and carbonate (Nelson 1981, Doi et al. 1998), but lowered with zinc (Mayer and Featherstone 2000) and fluorine. A discussion of dissolution mechanisms is available in a review by Dorozhkin (Dorozhkin 2002). The higher solubility of apatites may be linked to increased osteoclastic resorption, as found with carbonated apatite (Doi et al. 1999). 

---