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Mora S.,San Raffaele Scientific Institute | Puzzovio M.,San Raffaele Scientific Institute | Giacomet V.,University of Milan | Fabiano V.,University of Milan | And 5 more authors.

Reduced bone mineral density (BMD) and altered bone metabolism are common findings in HIV-infected patients. Increased bone formation has been described both in HIV-infected adults and children. Wnt ligands promote bone formation by stimulating osteoblast differentiation and their survival. Sclerostin and dickkopf factor 1 (DKK-1), Wnt antagonists, are important negative regulators of bone formation. We studied 86 HIV-infected patients whose ages ranged from 5.7 to 27.9 years. Patients were all on antiretroviral therapy, but seven who were naïve to treatment. Bone alkaline phosphatase (BAP), sclerostin, and DKK-1 were measured in serum by enzyme immunoassay. BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine and in the whole skeleton. Biochemical indexes were also measured in 143 healthy controls (age range 4.5–27.4 years). HIV-infected patients had lower than normal BMD (spine P < 0.005, and whole skeleton P < 0.03). BAP measurements were significantly higher in HIV-infected patients than controls (P ≤ 0.05). Sclerostin and DKK-1 concentrations were markedly lower than in controls (P ≤ 0.0006, and P ≤ 0.03, respectively). The serum concentration of both analytes of patients naïve to antiretroviral treatment was not different from that of treated patients. No correlations were found between sclerostin, DKK-1, and bone mineral measurements. Our data confirm the alteration of bone metabolism pathways in HIV-infected individuals. The lower concentration of Wnt antagonists is consistent with the increased bone formation markers. © 2015, Springer Science+Business Media New York. Source

Lombardi G.,Laboratory of Experimental Biochemistry & Molecular Biology | Sanchis-Gomar F.,Research Institute Hospital 12 Of Octubre I 12 | Perego S.,Laboratory of Experimental Biochemistry & Molecular Biology | Sansoni V.,Laboratory of Experimental Biochemistry & Molecular Biology | And 2 more authors.

Physical inactivity has been recognized, by the World Health Organization as the fourth cause of death (5.5 % worldwide). On the contrary, physical activity (PA) has been associated with improved quality of life and decreased risk of several diseases (i.e., stroke, hypertension, myocardial infarction, obesity, malignancies). Bone turnover is profoundly affected from PA both directly (load degree is the key determinant for BMD) and indirectly through the activation of several endocrine axes. Several molecules, secreted by muscle (myokines) and adipose tissues (adipokines) in response to exercise, are involved in the fine regulation of bone metabolism in response to the energy availability. Furthermore, bone regulates energy metabolism by communicating its energetic needs thanks to osteocalcin which acts on pancreatic β-cells and adipocytes. The beneficial effects of exercise on bone metabolism depends on the intermittent exposure to myokines (i.e., irisin, IL-6, LIF, IGF-I) which, instead, act as inflammatory/pro-resorptive mediators when chronically elevated; on the other hand, the reduction in the circulating levels of adipokines (i.e., leptin, visfatin, adiponectin, resistin) sustains these effects as well as improves the whole-body metabolic status. The aim of this review is to highlight the newest findings about the exercise-dependent regulation of these molecules and their role in the fine regulation of bone metabolism. © 2015 Springer Science+Business Media New York Source

Sansoni V.,Laboratory of Experimental Biochemistry & Molecular Biology | Vernillo G.,University of Milan | Vernillo G.,University of Verona | Vernillo G.,University of Calgary | And 8 more authors.

Bone and energy metabolisms regulation depends on a two-way street aimed at regulating energy utilization. Mountain ultra-marathons are highly demanding aerobic performances that deeply affect the whole body homeostasis. In this study we aimed to investigate and characterize the metabolic profile (in terms of hormones involved in energy metabolism), the inflammatory adipokines, and the bone turnover; in particular the osteocalcin-mediated response has been compared in experienced mountain ultra-marathons runners versus control subjects. Serum concentrations of specific markers of bone turnover (pro-collagen type I N-terminal propeptide, carboxylated/undercarboxylated osteocalcin), measured by enzyme-linked immunosorbent assay, and metabolic hormones (C-peptide, insulin, glucagon, glucagon-like peptide, gastric-inhibitory peptide, ghrelin, leptin, resistin, and visfatin), measured by fluorescent-based multiplex assay, were compared before and after a 65 km mountain ultra-marathons in 17 trained runners and 12 age-matched controls characterized by a low physical activity profile. After the mountain ultra-marathons, runners experienced a reduction in pro-collagen type I N-terminal propeptide, though it remained higher than in controls; while carboxylated osteocalcin remained unchanged. Among the metabolic hormones, only glucagon and leptin were different between runners and controls at rest. C-peptide and leptin decreased after the mountain ultra-marathons in runners; while glucagon, glucagon-like peptide 1, resistin, and visfatin were all increased. Uncarboxylated osteocalcin (and uncarboxylated/carboxylated osteocalcin ratio) was decreased and this highly correlated with insulin and C-peptide levels. In conditions of high energy expenditure, homeostasis is maintained at expenses of bone metabolism. Changes in the uncarboxylated osteocalcin clearly mark the global energy needs of the body. © 2016 Springer Science+Business Media New York Source

Lombardi G.,Laboratory of Experimental Biochemistry & Molecular Biology | Perego S.,Laboratory of Experimental Biochemistry & Molecular Biology | Luzi L.,University of Milan | Banfi G.,Laboratory of Experimental Biochemistry & Molecular Biology | Banfi G.,University of Milan

Osteocalcin (OC) is the main non-collagenous hydroxyapatite-binding protein synthesized by osteoblasts, odontoblasts, and hypertrophic chondrocytes. It has a regulatory role in mineralization and it is considered a marker of bone cell metabolism. Recent findings evidenced new extra-skeletal roles for OC, depicting it as a real hormone. OC shares many functional features with the common hormones, such as tissue-specific expression, circadian rhythm, and synthesis as a pre-pro-molecule. However, it has some peculiar features making it a unique molecule: OC exists in different forms based on the degree of carboxylation. Indeed, OC has three glutamic acid residues, in position 17, 21, and 24, which are subject to γ-carboxylation, through the action of a vitamin K-dependent γ-glutamyl carboxytransferase. The degree of carboxylation, and thus the negative charge density, determines the affinity for the calcium ions deposited in the extracellular matrix of the bone. The modulation of the carboxylation could, thus, represent the mechanism by which the body controls the circulating levels, and hence the hormonal function, of OC. There are evidences linking OC, and the bone metabolism, with a series of endocrine (glucose metabolism, energy metabolism, fertility) physiological (muscle activity) and pathological functions (ectopic calcification). Aim of this review is to give a full overview of the physiological roles of OC by collecting the newest experimental findings on this intriguing molecule. © 2014, Springer Science+Business Media New York. Source

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