Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. In a recent study [1], the authors show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in a gastrin receptor that affects acid secretion by parietal cells have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia.
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RANK ligand (RANKL) is produced by osteoblasts and is an essential mediator for osteoclast development. No study has examined in detail the direct skeletal consequences of excess RANKL on bone turnover, mineralization, architecture, and vascular calcification. The authors of a recent study [1] administered soluble RANKL continuously to mature rats and created a bone-loss model. Six-month-old Sprague-Dawley rats were assigned to three groups (n=12) receiving continuous administration of saline (VEH) or human RANKL (35 μg/kg/day or 175 μg/kg/day) for 28 days. Blood was collected routinely during the study. At sacrifice, hind limbs and aorta were removed and samples were analyzed.

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Major depressive disorder is a common condition and a major cause of disability. Besides mood changes, depression is associated with increased morbidity and non–suicide-related mortality. In addition to poor medical compliance and lifestyle factors, endocrine, immune, and autonomic dysregulation may play a causative role in producing medical illnesses in patients with major depression. An increased prevalence of low bone mineral density (BMD) has been reported in patients with major depressive disorder, mostly women. Moreover, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) may affect bone density and fracture risk per se, depending on the age of patients. The association of major depression disorder and BMD was investigated in a prospective study of bone turnover in which immune, pituitary-adrenal, and sympathetic biomarkers were measured [1]. The authors sought to determine whether premenopausal women with major depression had a higher prevalence of osteopenia and osteoporosis and of lower BMD than did healthy women. Baseline BMD was measured in 89 premenopausal women with major depression and 44 healthy control women enrolled in a prospective study of bone turnover. The BMD was measured by dual energy x-ray absorptiometry at the spine, hip, and forearm. Mean hourly levels of plasma 24-hour cytokines, 24-hour urinary free cortisol, and catecholamine excretion were measured in a subset of women.

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X-linked hypophosphatemia (XLH) is the archetypal vitamin D–resistant disease in humans, and the most common form of inherited rickets, with an incidence of approximately 1 in 20 000 live births. The disease is characterized by renal phosphate (Pi) wasting with resulting hypophosphatemia, abnormal vitamin D metabolism, defective bone and cartilage mineralization, dentine defects, and stunted growth. Recently, the gene involved in the pathogenesis of XLH was identified and designated as PHEX (the phosphate-regulating gene with homologies to endopeptidases on the X chromosome). The murine homolog of the human disease, the hyp-mouse, has a phenotype identical to that evident in patients with XLH, and is due to a large deletion in the 3′ region of the Phex gene. These findings suggest that a mutation in the PHEX/Phex gene is responsible for the phenotypic changes in patients with XLH and the hyp-mouse. Although PHEX/Phex expression occurs primarily in osteoblast lineage cells, transgenic Phex expression in hyp-mouse osteoblasts fails to rescue the phenotype, suggesting that Phex expression at other sites underlies XLH.
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The association between increased risk of hip fracture and low vitamin D status has long been recognized. However, the level of vitamin D required to maintain bone strength is controversial. In this study[1], the authors used a rodent model of vitamin D depletion to quantify the 25-hydroxyvitamin D (25D) levels required for normal mineralization. Six groups of 10-wk-old male Sprague-Dawley rats (n = 42) were fed a diet containing 0.4% calcium and various levels of dietary vitamin D3 for 4 months to achieve stable mean serum 25D levels ranging between 10 and 115 nmol/L. At 7 months of age, animals were killed, and the histomorphometry of distal and proximal femora and L2 vertebra was analyzed. Total RNA was extracted from whole femora for real-time RT-PCR analyses.
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Osteopetrosis is caused by a failure of osteoclasts to resorb bone tissue, resulting in bone marrow cavities becoming occluded. Osteopetrosis is a monogenetic disease and, whenever it occurs, can be traced to a gene essential to osteoclast function. The most severe form of human osteopetrosis is the malignant, infantile, autosomal recessive variant (ARO). ARO occurs because of specific mutations in genes responsible for osteoclast function. Despite a decrease in resorption, osteoclast numbers are normal or increased. These ‘‘osteoclast-rich’’ cases suggest that the osteoclast defect does not affect osteoclast formation but rather lies in their mature functional capacity. Providing osteoclast precursors via bone marrow transplantation successfully treats these patients.

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Bone alters its morphology and density in response to external loads. Lack of mechanical stimulation has been linked to bone loss in osteoporosis. Models of bone tissue predict that during loading, fluid flows through the compartments (lacunae) that house osteocytes within mineralized bone and through the channels (canaliculae) that connect lacunae to each other and to bone-forming osteoblasts at the bone surface. Experiments in cultured bone cells have shown that dynamic fluid flow stimulates osteogenic, and inhibits bone resorptive, responses. Primary cilia are solitary, immotile, microtubule-based organelles that grow from the centrosome and project from the cell surface in many vertebrate tissues, including bone. Primary cilia also function as flow sensors in kidney tubule epithelial cells where they mediate calcium entry through polycystin 2, a stretch-activated calcium channel. Mutations of polycystins cause polycystic kidney disease.

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Calcineurin is a protein phosphatase that regulates several physiological processes and is the target for cyclosporine A. Pharmacological inhibition of calcineurin by low concentrations of cyclosporin A increases osteoblast differentiation in vitro and bone mass in vivo. To determine whether calcineurin exerts direct actions on osteoblasts, the authors of a recent study [1] generated mice lacking a calcineurin regulatory subunit selectively in osteoblasts.
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Premenopausal women have one half the prevalence of calcium stone disease than men of comparable age. However, this sex difference disappears rapidly after the onset of menopause. Several studies have provided evidence that urinary calcium excretion increases at menopause, implicating a possible role for estrogen deficiency, and thereby increasing the risk for calcium-containing stones. In a recent study [1], the authors used the aromatase deficient (ArKO) mouse, a model of estrogen deficiency due to the lack of conversion of androgens into estrogens in peripheral tissues, to test the hypothesis that estrogen deficiency would increase urinary calcium excretion and alter the expression of molecular regulators of renal calcium reabsorption.

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Vitamin D plays an essential role in skeletal metabolism by binding to its nuclear steroid receptor, the vitamin D receptor (VDR). The heritability of bone mineral density (BMD) is well established, and the VDR gene is considered a prime candidate suggested to partially account for genetically controlled BMD variance in the population. The aim of a recent study was to reconstruct common haplotypes in the VDR 3’ untranslated region (UTR) and studied the association to BMD and risk of vertebral fractures in 3014 elderly men from Sweden and 2000 in Hong Kong, all participants of the global MrOS Study. To assess any functional implications of the VDR polymorphisms, the authors studied allele-specific expressions of the different VDR 3’ UTR haplotypes in the normal chromosomal context of 70 unrelated human trabecular bone samples. This was performed by quantitative genotyping of coding polymorphisms in RNA samples and in corresponding DNA samples isolated from the bone samples.

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