Osteoblast apoptosis

Calcitonin therapy results in decreased bone resorption. Osteoclasts have calcitonin receptors and calcitonin inhibits their activity. Sodium fluoride stimulates bone formation by unknown mechanisms. In women with osteoporosis, fluoride therapy produced an increased bone mineral density but no reduction in the rate of vertebral fractures. Other drugs known as selective estrogen receptor modulators (raloxifene, droloxifene, idoxifene, and levormeloxifene) may provide an alternative to estrogen replacement therapy (Chapter 34). Administration of low doses of PTH [or recombinant PTH( 1 -34)] does not affect serum calcium concentration, promotes bone formation, and increases mineral density. This anabolic action of PTH is probably mediated by decreasing osteoblast apoptosis. 

Secreted Frizzled-Related Protein-1 (SFRP-1) is a novel anabolic target for osteoporosis. Deletion of the SFRP-1 gene in mice leads to decreased osteoblast apoptosis and increased trabecular bone formation. An SFRP-1 inhibitor should be able to reverse osteoporotic bone loss by increasing osteoblast life and also allowing these cells to produce more bone. Compound 1 was identified... 

Hay et al., 2004). It also has been shown to promote apoptosis through a non-Smad protein kinase (PK) C-dependent pathway (Hay et al, 2001). The non-Smad PKC-dependant path increases BAX/BCL-2 and increases the amount of cytochrome c released from the mitochondria therefore which activates cas-pase-9 and the other effector caspases to initiate osteoblast apoptosis (Hay et al, 2001). TGF-Pl exerts a negative regulation of BMP-2 at transcription (Sykaras and Opperman, 2003). 

Hay, E., Lemonnier, J., Fromigu O., and Marie, P J. 2001. Bone morphogenetic protein-2 promotes osteoblast apoptosis through a Smad-independent, protein kinase C-dependent signaling pathway. Journal of Biological Chemistry, 276, 29028. 

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. 

Glucocorticoids decrease bone formation through decreased proliferation and differentiation, and enhanced apoptosis of osteoblasts. They also increase bone resorption, decrease calcium absorption, increase renal calcium excretion, and result in secondary hyperparathyroidism. 

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). 

Jilka RL, Weinstein RS, Bellido T, Parfitt AM, Manolagas SC (1998) Osteoblast programmed cell death (apoptosis) modulation by growth factors and cytokines. J Bone Miner Res 13 793-802... 

Gohel A, McCarthy MB, Gronowicz G (1999) Estrogen prevents glucocorticoid-induced apoptosis in osteoblasts in vivo and in vitro. Endocrinology 140 5339-5347... 

Conversely, the SAPK/JNK cascade, which is closely associated with apoptosis, is activated by sphingosine (Pyne et al, 1996). Exogenous sphingosine also activates caspase-7in a Bcl-x(L)-sensitive manner wha-eas caspase-8 was unaffected (Nava et al, 2000 Cuvillier et al, 2001). hi addition, sphingosine stimulates p38 MAPK in osteoblast-like cells (Kozawa et al, 2000) but not in oligodendrocytes where is produces lysis (Hida et al, 1999). p38 MAPK is up-stream of MAPKAP kinase-2 and the... 

Kozawa et al, 2000a and b). In both cell types, the p38 MAPK-specific inhibitor, SB203580, blocks SIP hsp27 induction and amplification of inositol phosphates, hi osteoblastic cells, PGE shmulates cyclic AMP formation and inhibits apoptosis. This appears to be mediated by a cyclic AMP-dependent modulation of SPHK and S IP production (Machwate etal., 1998)... 

Romanello M, Padoan M, Franco L, Veronesi V, Moro L, D Andrea P. 2001. Extracellular NAD+ induces calcium signaling and apoptosis in human osteoblastic cells. Biochem Biophys Res Commun 285 1226-31. 

Molinuevo, M.S., D.A. Barrio, A.M. Cortizo, and S.B. Etcheverry. 2004. Antitumoral properties of two new vanadyl(IV) complexes in osteoblasts in culture Role of apoptosis and oxidative stress. Can. Chemo. Pharm. 53 163-172. 

In hypocalcemia, the parathyroid increases its secretion of parathormone, resulting in enhanced liberation of Ca2+. Calcitonin transfers active osteoclasts into a resting state. Calcitonin given therapeutically relieves pain associated with neoplastic bone metastases and vertebral body collapse. Estrogens diminish bone resorption by (a) inhibiting activation of osteoclasts by osteoblasts and (b) promoting apoptosis of osteoclasts. 

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