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Bone Remodeling in Post-menopausal Osteoporosis

Department of Oral Cell Biology, Umeå University, Umeå SE-901 87, Sweden; Ulf.Lerner{at}odont.umu.se

View larger version (81K): [in a new window]   Figure 1. Unbalanced remodeling of the skeleton in post-menopausal osteoporosis because of excessive osteoclastic bone resorption and reduced capacity of osteoblasts to refill the resorption lacunae results in a decreased amount of bone tissue, loss of trabecular bone architecture, and, eventually, increased risk for fracture (compare normal bone in A and bone from an osteoporotic patient in B) [reproduced with permission of the American Society for Bone and Mineral Research from Dempster et al., J Bone Miner Res 1:15–21, 1986 ]. Unbalanced remodeling of the jawbones close to a chronic inflammatory process in the gingiva leads to loss of bone surrounding the roots of the teeth, and eventually to increased mobility and loss of teeth (C). (magnification not defined)

View larger version (34K): [in a new window]   Figure 2. Mineralized extracellular matrix in bone is covered by a non-mineralized extracellular matrix (osteoid) produced by osteoblasts, which form a one-cell layer covering all bone surfaces (A). Bone resorption is initiated by hormones, cytokines, or unknown molecules activating receptors present on osteoblasts, which leads to degradation of the osteoid (B) and increased expression of M-CSF and RANKL (C). M-CSF activates its cognate receptor c-fms on osteoclast progenitor cells, which results in proliferation and increased survival, and RANKL activates the receptor RANK, also on osteoclast progenitor cells, resulting in differentiation of these cells along the osteoclastic lineage (D). For osteoclast differentiation to occur, the immunoreceptor tyrosine-based activation motifs harboring molecules FcR and DAP12 need to be activated by hitherto-unknown ligands (D). The differentiation of the mononuclear osteoclast progenitor cells ends up with fusion to latent multi-nucleated osteoclasts (E), which finally become activated to bone-resorbing osteoclasts (F). The osteoclasts will attach to mineralized bone surface when the osteoblasts have retracted from the area to be resorbed (F).

View larger version (30K): [in a new window]   Figure 3. Remodeling of bone in a bone multi-cellular unit starts with osteoblastic activation of osteoclast differentiation, fusion, and activation (A,B). When resorption lacunae are formed, the osteoclast leaves the area, and mononucleated cells of uncertain origin appear and "clean up" the organic matrix remnants left by the osteoclast, also possibly forming the cementum line (dotted line) at the bottom of the lacunae (C). During the resorption process, coupling factors, including IGF-I and TGF- ß, are released from the bone extracellular matrix, and these growth factors contribute to the recruitment and activation of osteoblasts to the resorption lacunae (D). The osteoblasts will then fill the lacunae with new bone, and when the same amount of bone is formed as that being resorbed, the remodeling process is finished, and the mineralized extracellular matrix will be covered by osteoid and a one-cell layer of osteoblasts (E).

View larger version (25K): [in a new window]   Figure 4. In post-menopausal osteoporosis, the decrease of estrogen will lead to increased numbers of osteoclasts and, thus, enhanced numbers of bone multi-cellular units (A). As a consequence, the urinary excretion of calcium and collagen degradation products, such as deoxypyridinoline crosslinks, will be increased. Since more bone multi-cellular units are present in the skeleton of a post-menopausal woman, the number of active osteoblasts will be enhanced, and because of that, the serum level of osteocalcin will be increased (B). The more severe the osteoporosis, the more bone multi-cellular units will be present, and therefore the number of active osteoblasts and serum osteocalcin levels will be an indicator of "high turnover" osteoporosis. However, since the individual osteoblasts are less-well-functioning because of the lack of estrogen, the net effect of resorption and bone formation will be such that the amount of bone tissue will decrease.

View larger version (13K): [in a new window]   Figure 5. Activation of the receptor RANK starts with trimerization of the receptor and subsequent binding of different tumor necrosis factor receptor-associated factors (TRAFs), including the most important, TRAF6, to the cytoplasmic tail of RANK. This leads to activation of the inhibitor-B kinase (IKK) complex and subsequent phosphorylation of the nuclear factor-B (NF-B) inhibitor IB, which then becomes ubiquitinated and degraded in proteasomes. Released NF-B dimers translocate to the nucleus and bind to responsive elements in different genes. The activation of NF-B can be inhibited by estrogen by mechanisms the details of which are unknown. Activation of RANK also leads to activation of the mitogen-activated protein kinases (MAP kinases) p38, extracellular signal-regulated kinases (ERK) , and c-jun amino-terminal kinase (JNK), which then phosphorylate and activate the transcription factor AP-1. Activation of ERK and JNK has also been shown to be inhibited by estrogen. In addition to RANK activation, stimulation of either FcR or DAP12 is crucial for osteoclast differentiation. This pathway then leads to enhanced intracellular calcium and activation of calcineurin, which then dephosphorylates the transcription factor nuclear factor of activated T-cells 2 (NFAT2). It is not yet known if estrogen also affects this pathway. The importance of these pathways for osteoclastogenesis is shown by the findings that NF-B–/–, c-fos–/–, and NFAT2–/– mice all lack osteoclasts and are osteopetrotic.

View larger version (27K): [in a new window]   Figure 6. Osteoclast progenitor cell proliferation, differentiation, and fusion to bone-resorbing osteoclasts are enhanced during estrogen deficiency because of an increased RANKL/OPG ratio and the increased expression of M-CSF in periosteal osteoblasts and bone marrow stromal cells. Although it has been shown that estrogen can directly regulate M-CSF, it is not clear if the effect on RANKL and OPG expression is caused by a direct effect of estrogen, or if the increase is indirectly due to increased cytokines caused by a lack of estrogen.

View larger version (9K): [in a new window]   Figure 7. One hypothetical mechanism for the regulation of osteoclast formation during estrogen deficiency points to a crucial role of TNF--producing T-cells. Experimental observations in mice have shown that estrogen deficiency results in decreased expression of TGF-ß, which leads to enhanced expression of IFN- and subsequent augmented expression of class II transactivator in macrophages. This eventually causes increased numbers of TNF--producing T-cells. Thus, lack of TNF- signaling makes mice resistant to ovariectomy-induced increased osteoclastogenesis, similar to observations in mice lacking INF- signaling.