Osteoclast apoptosis

During bone formation, a series of sequential changes occur in cells in the osteoblast lineage, including osteoblast chemotaxis, proliferation and differentiation, which in turn is followed by formation of mineralised bone and cessation of osteoblast activity. The osteoblast changes are preceded by osteoclast apoptosis, which may be dependent on active TGF- 3 released from the resorbed bone. This is followed by chemotactic attraction of osteoblasts or their precursors to the sites of the resorption defect. Chemotactic attraction of osteoblast precursors is likely mediated by local factors produced during the resorption process. 

GAO Y H and YAMAGUCHI M (1999b) Siropressive effect of genistein on rat bone osteoclasts Apoptosis is induced through signalling. Biol Pharm Bull 22, 805-9. 

Fig. 7.3. Osteoclastogenesis after estrogen deficiency. Estrogen deprivation leads to an increase in the synthesis of RANKL for stromal/OB cells of the BM. This increase in the expression of RANKL leads to an increase in OCS. Estrogen deficiency also induces the synthesis and secretion of cytokines, such as IL-6 and M-CSF, that increase the number of preosteoclasts in the BM, and thus increases OCS. Nonetheless, certain cells of the immune system, such as monocytes and T-cells, intervene in the process when the supply of estrogens fails. These cells secrete IL-1 and TNF-a that are powerful inductors of OCS. When estrogens or agonists of estrogen receptors like raloxifene are administered, the synthesis and secretion of many of the mentioned cytokines diminish and the synthesis and liberation of OPG and TGF-/S are stimulated. These molecules inhibit OCS by inhibiting the RANKL/RANK signal pathway and by promoting osteoclast apoptosis...

In summary, IL-1 and TNF-a activate mature osteoclasts indirectly via a primary effect on osteoblasts and by inhibiting osteoclast apoptosis. In addition, they increase osteoclast formation either by directly stimulating the proliferation of osteoclast precursors or by increasing the pro-osteoclastogenic capacity of bone stromal cells. Although in vitro TNF-a and IL-1 can apparently induce the development of TRAP+ osteoclasts in the absence of RANKL/RANK, all data seem to indicate that TNF-a and IL-1 potentiate osteoclast development via the activation of common second messenger systems, such as NF-/cB activation, and that the effects on OCS require the RANKL/RANK system (Jones et al. 2002). 

Bisphosphonates (N-containing) structurally mimic endogenous pyrophosphate (see formulae), and like the latter are incorporated into the mineral substance of bone. During phagocytosis of the bone matrix, they are taken up by osteoclasts. There, the N-containing bisphosphonates inhibit prenyla-tion of G-proteins and thus damage the cells. Accordingly, osteoclast activity levels are lowered by alendronate and risedronate, while osteoclast apoptosis is promoted. The result is a reduction in bone resorption and a decreased risk of bone fractures. 

Kameda T, Miyazawa K, Mori Y, Yuasa T, Shiokawa M, Nakamaru Y, Mano H, Hakeda Y, Kameda A,and Kumegawa M (1996) Vitamin K2 inhibits osteoclastic bone resorption by inducing osteoclast apoptosis. Biochemical and Biophysical Research Communications 220, 515-19. 

Actions. These compounds are effective calcium chelators that rapidly target exposed bone mineral surfaces in vivo, where they can be released by bone-resorbing osteoclasts, resulting in inhibition of osteoclast function and osteoclast apoptosis. The bisphosphonates (alendronate, clodronate, etidronate, pamidronate, risedronate, tiludronate and zoledronate) inhibit the activation and function of osteoclasts and possibly directly stimulate formation of bone by the osteoblasts. They also bind strongly to hydroxyapatite crystals and, in high doses, can inhibit the mineralisation of bone. The doses at which effects on mineralisation occur are not related to antiresorptive efficacy. There is wide variation between these compoimds in terms of their capacity to inhibit... 

Although bisphosphonates prevent hydroxyapatite dissolution, their antiresorptive action is due to direct inhibitory effects on osteoclasts rather than strictly physiochemical effects. The antiresorptive activity apparently involves two primary mechanisms osteoclast apoptosis and inhibition of components of the cholesterol biosynthetic pathway. 

Pamidronate, a second-generation bisphosphonate, is 100-fold more potent than etidronate (Fig. 35.7) (6). It has been approved for the treatment of hypercalcemia of malignancy, for Paget s disease, and for osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma. When used to treat bone metastases, pamidronate decreases osteoclast recruitment, decreases osteoclast activity and increases osteoclast apoptosis (53). Erosive esophagitis has been reported with the use of pamidronate sodium. 

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