Estrogens are key hormones in bone remodeling. Estrogen deficiency in postmenopausal women frequently leads to osteoporosis, the most common skeletal disorder. Osteoporotic bone loss is the result of high bone turnover in which bone resorption outpaces bone formation. This imbalance can be ameliorated with bioavailable estrogens. Estrogens primarily act by regulating gene transcription via estrogen receptors (ERα, ERα). In mice, though ERα appears to be the major estrogen receptor, neither bone loss nor high bone turnover is detectable in ERα knock-out females. This unexpected maintenance of bone mass in female mutants is presumed to be due to unphysiologically elevated levels of other osteoprotective hormones, like androgens. Systemic defects in the hypothalamus caused by ER inactivation appear to impair the negative feedback system of hormone production. This leads to an excess in estrogen precursors, notably androgens. Thus, irrespective of the accumulating clinical and basic research data on the osteoprotective actions of estrogens, the molecular basis of this osteoprotection in females remains elusive. In this study [1], the authors report a critical role for ERα in mediating estrogen-dependent bone maintenance in female mice.
Bone modeling and remodeling are responsible for the construction of the skeleton during growth and its maintenance during adulthood. Bone remodeling involves the removal of a quantum of bone from a surface followed by the formation of new bone within the cavity created. Remodeling is carried out at spatially discrete foci by teams of cells that form the basic multicellular unit (BMU). The number of BMUs and the relative amounts of bone resorbed and formed within individual BMUs determine bone turnover. Assessment of remodeling balance and rate is achieved using static and dynamic histomorphometry. Estimation of remodeling balance requires measurement of the volume of bone formed (wall width) and resorbed (erosion depth) within individual BMUs. Measurement of erosion depth at completion of the resorptive phase of a remodeling cycle is problematic, imposing limitations on the accurate assessment of BMU balance. Remodeling rate is often expressed as the activation frequency, which represents the probability that a new remodeling cycle will be initiated at any point on the bone surface. Activation frequency represents the bone formation rate at surface level divided by the wall width. The histomorphometric derivation of activation frequency assumes that the remodeling rate is dependent on the duration of the remodeling cycle and the amount of bone formed in individual remodeling units. This implies that remodeling balance and remodeling rate are coregulated. A recent study [1] tested this assumption in normal human adult cancellous bone. Relationships between indices of bone formation at the basic multicellular unit (BMU) level (wall width and mineral apposition rate) and indices of remodeling rate (mineralizing perimeter and osteoid perimeter) were examined in iliac crest biopsies obtained from 57 healthy adults (24 men) 19 to 80 y of age.
Fibroblast growth factor FGF23: a new hormonal inhibitor of bone formation and mineralization
17/11/2009 in PhysiologyFibroblast 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.
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.
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.
The recent identification of the genes responsible for several human genetic diseases affecting bone homeostasis and the characterization of mouse models for these diseases indicated that canonical Wnt signaling plays a critical role in the control of bone mass [1]. A recent study [2] reports that the osteoblast-specific transcription factor Osterix (Osx), which is required for osteoblast differentiation, inhibits Wnt pathway activity. In calvarial cells of Osx-null embryos, expression of the Wnt antagonist Dkk1 was abolished, and that of Wnt target genes c-Myc and cyclin D1 was increased. Moreover, these studies demonstrated that Osx bound to and activated the Dkk1 promoter. In addition, Osx inhibited β-catenin-induced reporter activity and β-catenin-induced secondary axis formation in Xenopus embryos. Importantly, data from calvaria of Osx-null embryos indicate that Osx inhibited the Wnt pathway in osteoblasts in vivo. This study further shows that Osx disrupts binding of transcription factor TCF to DNA. This provides a likely mechanism for the inhibition by Osx of β-catenin transcriptional activity.
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Osteoclasts are cells of a hematopoetic lineage that resorb bone, and excessive activity of these cells can lead to low bone mass with an associated increased incidence of fractures. Osteoclast differentiation requires the transcription factor AP-1, which is a heterodimer of a Jun family member and a Fos family member.
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.
Adipocytes and osteoblasts derive from the same mesenchymal stem cells. During differentiation, gene expression programs decide the fate of these cells. One of the key mediators of adipogenesis is the nuclear hormone receptor PPAR-γ (peroxisome proliferator activated receptor γ). When stimulated by its ligand, PPAR-γ enhances expression of target genes that force differentiation into adipocytes. By contrast, expression of the major osteogenic determinants, the transcription factors Runx2 and Osterix, produce osteoblasts. The control and signaling mechanisms that lead to an adipogenic or osteogenic cell-lineage decision remain largely elusive. Canonical Wnt signalling is crucial for bone formation. In the Wnt signaling cascade, Wnt family members bind to their receptors on the cell membrane, and LRP5 (low density lipoprotein receptor related protein 5) or LRP6 are required as coreceptors (see Osteoscoop entitled “PTH does not need Lrp5 to stimulate bone formation in mice”). Activation of the receptor complex leads to the intracellular accumulation of β-catenin, and this increase leads to translocation of β-catenin to the nucleus where it serves as a cofactor for a transcription factor. Disruption of the canonical Wnt signalling cascade severely impairs bone formation. For example, mutations in LRP5 result in altered bone mass in mice and humans. Deletion of β-catenin in osteoblasts also leads to multiple skeletal defects.
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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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Most used keywords
β-catenin age BMD bone bone density bone density test bone formation bone fracture bone loss bone marrow bone remodeling bone resorption bone strength breast cancer calcium cardiovascular cardiovascular disease cell cell bone marrow cholesterol Clinical data diabetes disease epidemiology fracture fracture risk FRAX heart heart disease hip fracture mesenchymal stem cells neuromedin U osteoblast osteoblast differentiation osteoclast osteoporosis osteoprotegerin osterix ovariectomy RANKL residual lifetime risk risk factors sclerotin survival weight loss