Sclerostin mediates bone response to mechanical unloading
Reduced mechanical loading leads to bone loss, as evidenced by disuse osteoporosis in bedridden patients and astronauts. Osteocytes, which are terminally differentiated osteoblasts, have been identified as the major cells responsible for mechanotransduction. However, the mechanism underlying the response of bone to mechanical unloading remains poorly understood. The Wnt/β-catenin pathway is implicated in bone formation. Its activation requires the interaction between Wnt, its receptor Frizzled, and a coreceptor (either low-density lipoprotein (LDL) receptor–related proteins 5 or 6 (LRP5 or LRP6)) and results in the stabilization of the transcription factor β-catenin. Wnt/β-catenin pathway activation in the osteoblast lineage favors osteoblast differentiation and osteocyte formation. Sclerostin, a secreted protein encoded by the Sost gene, binds Wnt co-receptors LRP5 and LRP6 and inhibits Wnt/β-catenin signaling. Sost is nearly exclusively expressed in osteocytes in adult bone and its expression is responsive to mechanical stimulus. However, the role of sclerostin in bone response to mechanical stress remains unknown.
Activating transcription factor 4 regulates osteoclast differentiation
Skeletal integrity requires a delicate balance between osteoblast and osteoclast activity. Excessive osteoclastogenesis results in bone destruction whereas reduced osteoclastogenesis causes osteopetrosis. Osteoclasts originate from cells of the monocyte/macrophage lineage and their formation and maturation is tightly regulated. M-Csf is a growth factor which regulates the early phase of osteoclast lineage commitment. Binding of M-Csf to its receptor on bone marrow monocytes activates Pi3k/Akt signaling pathway and Rank gene transcription. Then, Rank ligand binds to Rank on osteoclast precursors and induces the expression of Nfat1c, a crucial transcriptional factor for osteoclast differentiation. Activating transcriptional factor 4 (Atf4) is a critical factor for osteoblasts differentiation, but its cell autonomous function in osteoclast differentiation has not been studied.
TGF-β1 couples bone resorption with formation through migration of bone mesenchymal stem cells
Bone remodeling depends on the precise coordination of bone resorption and subsequent bone formation. Coupling of bone resorption and formation is believed to occur through the release, during osteoclastic bone resorption, of factors that have been trapped in the bone matrix during its formation. These factors direct the migration of bone mesenchymal stem cells to the bone resorptive surface, where they differentiate into osteoblasts. TGF-β1, one of the most abundant cytokine in bone matrix, is synthesized as a large precursor molecule, which is cleaved into active TGF-β1 and latency-associated protein (LAP) which remains linked to TGF-β1 as it deposits in bone. This complex, called latent TGF-β1, cannot activate its receptor and has to be dissociated to release active TGF-β1. TGF-β1 gene is mutated in Camurati-Engelmann disease (CED), a rare form of skeletal disease characterized by a progressive diaphyseal dysplasia, but all the mutations have been mapped to LAP and none of them altered TGF-β1 secretion or activity in vitro. Thus, the precise role TGF-β1 in bone remodeling remained unclear.
Osteoclastic Metabolism of 25(OH)-Vitamin D3: A Potential Mechanism for Optimization of Bone Resorption
Vitamin D plays an important role in the maintenance of optimal bone mineralization. Besides its role in phosphate and calcium homeostasis, it is now recognized that vitamin D acts directly on bone cells. 1alpha,25 hydroxyvitamin D3 (1,25D), which is produced by the hydroxylation of 25 hydroxyvitamin D3 (25D) by the enzyme 1-alpha-hydroxylase, directly stimulates bone resorption and increases osteoblast-mediated osteoclastogenesis. The major site of vitamin D hydroxylation is the kidney. However, several cell types, including osteoblasts, express 1-alpha-hydroxylase, thereby enabling local production of the fully active 1,25D. Whether osteoclasts are able to convert 25D directly to 1,25D and the function of such a conversion in bone homeostasis remain undetermined.
Pregnancy upregulates intestinal calcium absorption and skeletal mineralization independently of the vitamin D receptor
Without the vitamin D receptor (VDR), adult mammals develop reduced intestinal calcium absorption, rickets, and osteomalacia. Intestinal calcium absorption normally increases during the pregnancy so that the mother can supply sufficient calcium to her foetus. The maternal skeleton is rapidly resorbed during lactation to provide calcium needed for milk; lost bone mineral content is completely restored after weaning. Recently [1], the authors studied VDR null mice to determine whether these adaptations during pregnancy and lactation require the vitamin D receptor.
 Download here the slide set presented by Prof. Friedlander, on Thursday, November 10th. |
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