Postmenopausal osteoporosis, T cells, and immune dysfunction

Because of its dramatic appearance, the osteoclast has been long recognized as a bonedegrading cell, but its ontogeny remained enigmatic until the late 1970s when Donald Walker demonstrated that mice with enhanced bone mass caused by dysfunctional osteoclasts are cured by parabiosis or infusion of spleen cells, laying the foundation for the generation of osteoclasts, in vitro , from marrow preparations. The next critical step came in 1990, when Tatsuo Suda's group (1) demonstrated that macrophages, placed in proper culture conditions, differentiate into bone fide osteoclasts, establishing membership of the bone resorptive cell in the monocyte/macrophage family. Unexpectedly, however, commitment of macrophages to the osteoclast phenotype required contact of the precursor cell with marrow mesenchymal cells. In 1998, the key, stromal cell-residing, osteoclastogenic molecule was identified as RANK ligand (RANKL), a member of the tumor necrosis factor (TNF) superfamily (2). Postmenopausal osteoporosis, which follows ovarian failure, reflects an absolute acceleration in the rate of bone resorption due to increased osteoclast recruitment. The realization that the osteoclast is a relative of the macrophage, a cell that secretes and is regulated by inflammatory cytokines, raised the possibility that the same molecules also modulate the bone resorptive cell and, in fact, TNF-α and IL-1 proved agonistic in this regard. As a consequence, Pacifici hypothesized in 1987 (3) that estrogen deprivation enhances the production of proresorptive inflammatory cytokines and established that such is the case by demonstrating that IL-1 and TNF-α are secreted by peripheral blood mononuclear cells derived from osteoporotic women. Neutralization of TNF- α and IL-1 protects against ovariectomy-induced bone loss. These experiments, however, raised a challenging conundrum. Whereas generation of osteoclasts from bone marrow macrophages required the presence of stromal cells (1), this was not true when the resorptive polykaryon was derived from circulating monocytes, suggesting an alternative source of …