Osteoporosis is an age-related skeletal disease characterized by a rapid and sustained loss of bone density, and an increased susceptibility to bone fractures. The leading cause of osteoporosis in women is a reduction in estrogen production following menopause.1 Estrogen deficiency is associated with a disruption of bone homeostasis caused by an increase in the number and activity of bone-resorbing osteoclasts. Under normal physiological conditions, bone structure is maintained by a coupling of osteoclast activity with the activity of bone-forming osteoblasts. Osteoblasts regulate osteoclast differentiation through the expression of RANK L and M-CSF. RANK L binding to RANK on osteoclast precursor cells promotes their differentiation. Factors that affect this process stimulate changes in bone mass that can lead to a variety of bone disorders. While the connection between estrogen deficiency and osteoporosis has been known for some time, cellular factors responsible for this effect are still being elucidated.
||Two Primary Mechanisms Promote Increased Osteoclastogenesis and Bone Resorption in the Absence of Estrogen. Under estrogen-deficient conditions, T cells produce elevated levels of proinflammatory cytokines including TNF-alpha, IL-1, and IL-6. These cytokines promote increased RANK L expression on osteoblasts and stromal cells, which leads to osteoclast differentiation in the presence of M-CSF. In addition, CCR2 expression on osteoclast precursor cells is upregulated in the absence of estrogen. CCR2 signaling promotes the expression of RANK on these cells and increases their osteoclastogenic potential. Both mechanisms may contribute to the pathogenesis of postmenopausal osteoporosis.
Proinflammatory cytokines are one critical group of proteins that contribute to the bone-wasting effects associated with estrogen deficiency. Studies in ovariectomized mice, a model of postmenopausal osteoporosis, demonstrated that estrogen deficiency leads to an upregulation of IL-1, IL-6, M-CSF, and TNF-alpha, which enhances bone resorption in part by increasing the pool of preosteoclasts in the bone marrow.1 TNF-alpha, in particular, plays a central role. It not only induces the expression of RANK L on osteoblasts and stromal cells, but is also involved in regulating the production of other osteoclastogenic cytokines. 1, 2, 3, 4, 5, 6 Increased T cell activity largely accounts for the high levels of TNF-alpha associated with estrogen deficiency.3, 5, 7 Significantly, both TNF-deficient and T cell-deficient mice are protected from ovariectomy-induced bone loss.3, 5 While adoptive transfer of wild-type T cells into T cell-deficient mice re-establishes estrogen-deficient bone loss, transfer of T cells from TNF-deficient mice does not.5 Although bone metabolism may differ significantly in mice and humans, strong evidence suggests that increased T cell expression of TNF-alpha and RANK L is involved in promoting estrogen-deficient bone loss in humans as well. 8, 9, 10
C-C chemokine receptor 2 (CCR2) is another factor that was recently demonstrated to be involved in mediating bone loss in the absence of estrogen11 CCR2 is a G protein-coupled receptor that is activated by chemokines such as monocyte chemoattractant protein-1 and -3 (MCP-1 and MCP-3). Both CCR2 and MCP-1 were previously shown to be induced during osteoclast differentiation, but little was known about the effects of CCR2-dependent signaling on bone loss.12, 13, 14 Using CCR2-deficient mice, Binder et al. discovered that there is a significant increase in bone mass and stability in the absence of CCR2.11 This increase is attributable to a defect in the differentiation of bone marrow macrophages (BMMs) into mature osteoclasts in CCR2-/- mice. While wild-type and CCR2-deficient mice had similar numbers of BMMs expressing CD11b, a marker of preosteoclasts, BMMs from CCR2-deficient mice had a lower percentage of RANK-positive cells and reduced expression of RANK-dependent genes. Furthermore, treatment with MCP-1 or MCP-3 induced the expression of RANK in wild-type BMMs, but had no effect on CCR2-deficient BMMs. These results support the involvement of CCR2 in the regulation of RANK-dependent osteoclast differentiation. To determine if CCR2 contributes to bone loss under estrogen-deficient conditions, wild-type and CCR2-deficient mice were examined following ovariectomy.
In wild-type mice, ovariectomy led to an increase in both the number of CD11bhigh preosteoclasts and the expression of CCR2 and RANK on these cells. In CCR2-deficient mice, there was a similar increase in the number of CD11bhigh preostoclasts, but a less significant increase in RANK expression. More importantly, lack of CCR2 protected against ovariectomy-induced bone loss, indicating that CCR2 signaling may also contribute to the pathogenesis of postmenopausal osteoporosis. Collectively, these studies suggest that bone resorption under estrogen-deficient conditions is stimulated by two mechanisms: 1) an elevated number of TNF-alpha-producing T cells, which promote RANK L-dependent osteoclastogenesis, and 2) an increase in the expression of CCR2 on preosteoclasts, which induces RANK expression and increases the likelihood of osteoclast differentiation.
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