Connexin43 (Cx43) is involved in bone development, but its role in adult bone homeostasis remains unknown. To overcome the postnatal lethality of Cx43 null mutation, we generated mice with selective osteoblast ablation of Cx43, obtained using a Cx43^fl allele and a 2.3-kb fragment of the α₁(I) collagen promoter to drive Cre in osteoblasts (ColCre). Conditionally osteoblast-deleted ColCre;Cx43^–/fl mice show no malformations at birth, but develop low peak bone mass and remain osteopenic with age, exhibiting reduced bone formation and defective osteoblast function. By both radiodensitometry and histology, bone mineral content increased rapidly and progressively in adult Cx43^+/fl mice after subcutaneous injection of parathyroid hormone (PTH), an effect significantly attenuated in ColCre;Cx43^–/fl mice, with Cx43^–/fl exhibiting an intermediate response. Attenuation of PTH anabolic action was associated with failure to increase mineral apposition rate in response to PTH in ColCre;Cx43^–/fl, despite an increased osteoblast number, suggesting a functional defect in Cx43-deficient bone-forming cells. In conclusion, lack of Cx43 in osteoblasts leads to suboptimal acquisition of peak bone mass, and hinders the bone anabolic effect of PTH. Cx43 represents a potential target for modulation of bone anabolism.

We studied the function of osteoblast cadherins in vivo by transgenic expression of a truncated N-cadherin with dominant-negative action, driven by an osteoblast-specific promoter (OG2-NcadΔC). During the first 3 months of life, bone mineral density was reduced, whereas percent body fat was increased in transgenic animals compared with wild-type littermates, with associated decreased bone formation rate and osteoblast number, but normal osteoclast number. Osteoblast differentiation was delayed in calvaria cells isolated from transgenic mice. Likewise, the number of osteoblast precursors in bone marrow stromal cells from OG2-NcadΔC mice was decreased compared with wild-type cultures, whereas the number of adipogenic precursors was increased. In vitro, a transcriptionally active β-catenin mutant reversed the delay in osteoblast differentiation and the exuberant adipogenesis. Thus, in vivo disruption of cadherin function hinders osteoblast differentiation and favors, indirectly, bone marrow progenitor cell commitment to the alternative adipogenic lineage via interference with β-catenin signaling. This results in decreased bone formation, delayed acquisition of peak bone mass and increased body fat.

OBJECTIVE—Kinins mediate pathophysiological processes related to hypertension, pain, and inflammation through the activation of two G-protein–coupled receptors, named B₁ and B₂. Although these peptides have been related to glucose homeostasis, their effects on energy balance are still unknown. RESEARCH DESIGN AND METHODS—Using genetic and pharmacological strategies to abrogate the kinin B₁ receptor in different animal models of obesity, here we present evidence of a novel role for kinins in the regulation of satiety and adiposity. RESULTS—Kinin B₁ receptor deficiency in mice (B₁^−/−) resulted in less fat content, hypoleptinemia, increased leptin sensitivity, and robust protection against high-fat diet–induced weight gain. Under high-fat diet, B₁^−/− also exhibited reduced food intake, improved lipid oxidation, and increased energy expenditure. Surprisingly, B₁ receptor deficiency was not able to decrease food intake and adiposity in obese mice lacking leptin (ob/ob-B₁^−/−). However, ob/ob-B₁^−/− mice were more responsive to the effects of exogenous leptin on body weight and food intake, suggesting that B₁ receptors may be dependent on leptin to display their metabolic roles. Finally, inhibition of weight gain and food intake by B₁ receptor ablation was pharmacologically confirmed by long-term administration of the kinin B₁ receptor antagonist SSR240612 to mice under high-fat diet. CONCLUSIONS—Our data suggest that kinin B₁ receptors participate in the regulation of the energy balance via a mechanism that could involve the modulation of leptin sensitivity.

Background/Objectives The association between muscle mass, strength and physical performance has been established in the elderly with co-morbidities. In this study, lean and fat mass, bone mineral density, knee extension and flexion strength and physical ability tests in healthy independent elderly women were investigated. Main determinants of lean mass, strength and physical ability were determined searching for predictors of healthy aging. Methods A total of 100 healthy women aged ≥ 65 years considered independent and active were invited. Bone mass and body composition were assessed by DXA. The strength of the lower limb was assessed by isokinetic dynamometry, and physical ability was measured by: Timed Up and Go (TUG), Berg Balance Test (BBT) and Dynamic Gait Index (DGI). Results Women were on average 70.8±4.92 years old, had BMI of 27.38±5.11 kg/m2 and fat mass of 26.96±9.62 kg or 40.65±8.06%. Total lean mass and appendicular lean mass (ALM) were 35.38±4.83 kg and 15.32±2.26 kg, respectively, while relative skeletal mass index (RSMI) was 6.51±0.77 kg/m2. Age did not correlate significantly with ALM. Age and ALM were the main determinants of the strength of the lower limb (p<0.001) while age and strength of the lower limb were significantly associated with the performance on the physical tests (p<0.001). Conclusion Age has a negative impact on the strength and the physical performance in independent healthy women without co-morbidities. Physical ability tests are positively influenced by the strength of the lower limb. These relationships suggest that muscle strength should be the parameter to be prioritized when preparing for healthy aging.

We aim to evaluate the prevalence of vitamin D deficiency in patients with systemic lupus erythematosus (SLE) and investigate the association between total, free and bioavailable vitamin D serum concentrations and disease activity. Patients with SLE (ACR 1997) consecutively seen at UNIFESP’s outpatient’s clinics had disease activity measured after clinical and laboratory evaluation using SLEDAI (Systemic Lupus Erythematosus Disease Activity Index). 25-hydroxyvitamin D (25(OH)D) serum concentrations measured by chemiluminescence and vitamin D binding protein (DBP) measured by ELISA were used to calculate free and bioavailable vitamin D. Healthy blood donors were used as controls. A total of 142 patients (71.4%) had 25(OH)D serum concentrations below 30 ng/mL. Total 25(OH)D serum concentration was associated with disease activity categorized in 5 continuous groups of SLEDAI. 25(OH)D serum concentrations were higher among patients with SLEDAI 1–5 and lower in those with severe activity (SLEDAI≥20) (p <0.05). On the other hand, no statistically significant difference was observed for DBP, free and bioavailable vitamin D measurements in the disease activity subgroups evaluated. Vitamin D deficiency is highly prevalent among patients with SLE and was associated with higher disease activity. DBP serum level and calculation of free and bioavailable vitamin D were not associated with SLE disease activity.