Fibroblast growth factor (FGF)23 is a circulating peptide produced primarily in bone which acts on kidney as a systemic phosphaturic factor; high levels result in rickets and osteomalacia. However, it remains unclear whether FGF23 acts locally and directly on bone formation. In order to address this question, the authors of a recent study [1] overexpressed human FGF23 in a stage-specific manner during osteoblast development in fetal rat calvaria cell cultures by using the adenoviral overexpression system and analyzed its effects on osteoprogenitor proliferation, osteoid nodule formation, and mineralization. Bone formation was also measured by calcein labeling in parietal bone organ cultures. Finally, the role of tyrosine phosphorylation of FGF receptor in mineralized nodule formation was also addressed.

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Osterix (Osx) is essential for osteoblast differentiation and bone formation, because mice lacking Osx die within 1 hour of birth with a complete absence of intramembranous and endochondral bone formation. Perinatal lethality caused by the disruption of the Osx gene prevents studies of the role of Osx in bones that are growing or already formed.
Here [1], the function of Osx was examined in adult bones using the time- and site-specific inactivation of this gene only in osteoblasts. Even though no bone defects were observed in newborn mice, Osx inactivation induced osteopenia in growing mice. BMD and bone-forming rate were decreased in lumbar vertebra, and the cortical bone of the long bones was thinner and more porous with reduced bone length. The trabecular bones were increased, but they were immature or premature. The expression of early marker genes for osteoblast differentiation such as Runx2, osteopontin, and alkaline phosphatase was markedly increased, but the late marker gene, osteocalcin, was decreased. However, no functional defects were found in osteoclasts.

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An imbalance in bone formation relative to bone resorption results in the net bone loss that occurs in osteoporosis and inflammatory bone diseases. Although it is well known that RANKL/RANK stimulate bone resorption by activating nuclear factor-kB (NF-kB) in osteoclasts, the molecular mechanisms that mediate impaired bone formation are poorly understood.

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Animal studies provided evidence that osteoclast-derived ephrinB2 can act through its receptor, EphB4, in osteoblasts to promote osteoblast differentiation and that reverse signaling by osteoblast-derived EphB4 can suppress the formation of osteoclast precursors in a contact-dependent process. With the aim of identifying new pathways and genes regulated by PTH and PTH-related protein (PTHrP) in osteoblasts, this study [2] was carried out using a mouse marrow stromal cell line, Kusa 4b10, that acquires features of the osteoblastic phenotype in long-term culture conditions. After the appearance of functional PTH receptor 1 (PTHR1) in Kusa 4b10 cells, they were treated with either PTH or PTHrP, and RNA was subjected to whole mouse genome array. The microarray data were validated using quantitative real-time RT-PCR on independently prepared RNA samples from differentiated Kusa 4b10, UMR106 osteosarcoma cells, and primary mouse calvarial osteoblasts, as well as in vivo using RNA from metaphyseal bone after a single PTH injection.

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Bone remodeling, which is affected in osteoporosis, comprises two phases: bone formation by matrix-producing osteoblasts and bone resorption by osteoclasts. The demonstration that the anorexigenic hormone leptin inhibits bone formation through a hypothalamic relay suggests that other molecules that affect energy metabolism in the hypothalamus could also modulate bone mass. Neuromedin U is an anorexigenic neuropeptide that acts independently of leptin through poorly defined mechanisms.

A recent study [1] shows that neuromedin U-deficient mice have high bone mass owing to an increase in bone formation; this is more prominent in male mice than female mice. Physiological and cell-based assays indicate that neuromedin U acts in the central nervous system, rather than directly on bone cells, to regulate bone remodeling.
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One pathway identified by human genetics as a major player in the control of bone formation is the Wnt signaling pathway [1]. This pathway is crucial for the specification of cell fates, regulation of cell growth, differentiation, and apoptosis. Wnt ligands are secreted lipid-modified glycoproteins that signal through a receptor complex comprising a member of the Frizzled family of seven transmembrane domain receptors, and the co-receptor lipoprotein-receptor related proteins (LRPs) 5 or 6.
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