Sex Steroids, Cytokines and the Bone Marrow: New Concepts on the Pathogenesis of Osteoporosis

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Abstract
Osteoclasts and osteoblasts, originating in the bone marrow from haemopoietic progenitors and mesenchymal stromal cells, respectively, are responsible for the remodelling of the skeleton throughout adult life. Upon loss of sex steroids, the production of osteoclasts in the bone marrow is increased. This is mediated by an increase in the production of interleukin 6 (IL-6), as well as an increase in the sensitivity of the osteoclastic precursors to the action of cytokines such as IL-6, owing to an up-regulation of the gp130 signal transduction pathway. Consistent with this, oestrogens as well as androgens inhibit IL-6 production through an indirect effect of their specific receptors on the transcriptional activity of the IL-6 gene promoter, and inhibit the expression of the gp130 gene. With advancing age, the ability of the marrow to maintain the high rate of osteoclastogenesis caused by the acute loss of sex steroids is diminished. This is probably the result of the negative effect of senescence on the ability of the marrow to produce stromal/osteoblastic cells, which provide the essential support for osteoclastogenesis. These observations suggest that inappropriate production of osteoclasts or inadequate production of osteoblasts in the bone marrow are fundamental cellular changes in the pathogenesis of postmenopausal and senescence-associated osteoporosis, respectively.

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