Smoking is associated with lower areal bone mineral density and higher fracture risk, although most evidence has been derived from studies in elderly subjects. This study [1] investigates smoking habits in relation to areal and volumetric bone parameters and fracture prevalence in young, healthy males at peak bone mass. Healthy male siblings (n=677) at the age of peak bone mass (25 to 45 years) were recruited in a cross-sectional population-based study. Trabecular and cortical bone parameters of the radius and cortical bone parameters of the tibia were assessed using peripheral quantitative computed tomography (pQCT). Areal bone mass was determined using dual energy X-ray absorptiometry (DXA). Sex steroids and bone markers were determined using immunoassays. Prevalent fractures and smoking habits were assessed using questionnaires.

Self-reported fractures were more prevalent in the current and early smokers than in the never smokers (P<.05), with a fracture prevalence odds ratio for early smokers of 1.96 after adjustment for age, weight, educational level, and alcohol use and exclusion of childhood fractures. Current smoking was associated with a significantly larger endosteal circumference and a decreased cortical thickness at the tibia.
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MEPE (Matrix Extracellular PhosphoglycoprotEin) is a protein secreted by osteoblasts and osteocytes. Its synthesis is increased in several phosphate and bone-mineral metabolic disorders such as hypophosphatemic rickets and oncogenic hypophosphatemic osteomalacia. Under normal circumstances, MEPE is cleaved to release a peptide which acts as an inhibitor of bone mineralization. MEPE may be a substrate for an enzyme called PHEX, and PHEX may prevent proteolysis of MEPE and release of the peptide which inhibits bone mineralization. In patients with X-linked hypophosphatemic rickets (XLH) and in mice with the Hyp mutation, PHEX is mutated and therefore cannot bind to MEPE. This results in the release of MEPE into the circulation, thereby causing hypophosphatemia and renal Pi wasting. To elucidate the causative role of MEPE in these disorders, the authors of a recent study [1] created a murine model overexpressing MEPE protein in bone.

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The absence of significant changes in bone mineral density caused by decline or overproduction of calcitonin (CT) in humans has raised the question of whether the pharmacological action of CT as an inhibitor of bone resorption is also of physiological relevance.

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Fat mass may be a causal determinant of bone mass, but the evidence is conflicting, possibly reflecting the influence of confounding factors. The recent identification of common genetic variants related to obesity in children provides an opportunity to implement a Mendelian randomization study of obesity and bone outcomes, which is less subject to confounding and several biases than conventional approaches. Genotyping was retrieved for variants of two loci reliably associated with adiposity (the fat mass and obesity-related gene FTO and that upstream of the MC4R locus) within 7470 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) who had undergone total body DXA scans at a mean of 9.9 yr [1]. Relationships between both fat mass/genotypes and bone measures were assessed in efforts to determine evidence of causality between adiposity and bone mass.

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Oxytocin, a hypothalamic nanopeptide secreted into the circulation from the posterior pituitary, is indispensable for lactation. It acts on a G protein-coupled receptor, the expression of which in reproductive tissues is regulated by sex steroids and oxytocin itself. In humans and rodents, plasma oxytocin levels are elevated maximally during suckling.

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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.

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Loss- 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.

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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.

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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.

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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).

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