The development and maintenance of the mammalian skeleton are controlled by actions of morphogens and growth factors on bone cells. Skeletal growth factors such as insulin-like growth factor-1 (IGF-1) affect bone formation and induce osteoblast proliferation and lifespan by activating antiapoptotic pathways, increasing cell proliferation, and influencing differentiation. A key control point in many antiapoptotic pathways is a kinase named phosphatidylinositol (PI) 3-kinase (PI3K), which is activated in response to various extracellular signals and leads to generation to lipidic second messengers. A key downstream target of this pathway is another kinase named Akt. When activated, Akt promotes cell growth and cell survival by regulating numerous downstream pathways.
Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum
19/01/2010 in PhysiologyLoss- and gain-of-function mutations in the broadly expressed gene LDL receptor-related protein 5 (Lrp5) affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of β-catenin does not affect bone formation.
Instead, the authors of this study [1] show here that Lrp5 inhibits expression of tryptophan hydroxylase 1 (Tph1), the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a β-catenin-independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation.
The leptin regulation of bone remodeling, has been documented through studies of loss-of-function mutations of this hormone or of its receptor in mice and humans (see Osteoscoop Newsletter N°14, 15, 34, 37). However, unanswered questions remain. For instance, it has been assumed but not formally demonstrated that this regulation occurs through neuronal means. Likewise, it has not been possible until now to dissociate the influence leptin exerts on appetite and energy expenditure from this function.
Src family kinases (SFKs) are nonreceptor tyrosine kinases that are promiscuous in their impact on events such as growth, differentiation, cytoskeletal organization, and survival. One member of this family, c-Src kinase, is a rate-limiting activator of osteoclast function and Src inhibitors are therefore candidate antiosteoporosis drugs. By affecting M-CSF-induced signaling, c-Src is central to osteoclast activity, but not differentiation. The authors of a recent study [1] found that Lyn, another member of Src family kinases is, in contrast, a negative regulator of osteoclastic bone resorption.
Low-density lipoprotein receptor–related protein 5 (Lrp5) is a membrane protein acting as a coreceptor in canonical Wnt signaling. Lrp5 increases osteoblast proliferation, differentiation, and function. The purpose of a recent study [1] was to use Lrp5-deficient mice to evaluate the potential role of this gene in mediating the bone anabolic effects of parathyroid hormone (PTH).
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.
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