Hepcidin1 knockout mice display defects in bone microarchitecture and changes of bone formation markers.

Iron accumulation is a risk factor of osteoporosis; mechanisms leading to iron-related bone loss are not fully determined. We sought to better understand the effect of chronic iron accumulation on bone over the life span in a mouse model. Hepcidin1 knockout (Hepc1(-/-)) male mice and their littermate control wild type (WT) mice at 7 months old were used in this study. Serum iron and ferritin as well as iron contents in liver and femur were significantly increased in Hepc1(-/-) mice compared to WT mice. We found that Hepc1(-/-) mice had a phenotype of low bone mass and alteration of the bone microarchitecture, most likely caused by a decreased osteoblastic activity. Cell culture studies indicated that chronic iron accumulation decreased bone formation, probably by affecting bone morphogenetic protein signaling.

The GDF11-FTO-PPARγ axis controls the shift of osteoporotic MSC fate to adipocyte and inhibits bone formation during osteoporosis.

During osteoporosis, the shift of bone mesenchymal stem cell (BMSC) lineage commitment to adipocyte leads to the imbalance between bone mass and fat, which increases the risk of fracture. The mechanism underlying this process is not fully understood. Fat mass and obesity-associated protein (FTO) is an RNA demethylase that demethylates various methylated nucleic acids and participates in various physiological and pathological processes. Here we identified FTO as a regulator for BMSC fate determination during osteoporosis. FTO was up-regulated in bone marrow during aging or osteoporosis in human and mice in a GDF11(growth differentiation factor 11)-C/EBPα-dependent mechanism. The expression of FTO was also up-regulated during adipocyte differentiation of BMSCs whereas its expression was down-regulated during osteoblast differentiation. Gain-of-function and loss-of-function experiments showed that FTO favored the BMSCs to differentiate to adipocytes rather than osteoblasts. Further mechanism study demonstrated that FTO bound and demethylated the mRNA of the Peroxisome proliferator-activated receptor gamma (Pparg), leading to the increase in the expression of Pparg mRNA. Reversely, Pparg knockdown blocked the function of GDF11-FTO during osteoblast differentiation of BMSCs. Furthermore, conditionally genetic knockout of Fto in osteoblasts inhibited the development of osteopenia in mice. Collectively, our findings demonstrated that GDF11-FTO-Pparg axis promoted the shift of osteoporotic BMSC fate to adipocyte and inhibited bone formation during osteoporosis.

Cigarette smoking and risk of hip fracture in women: a meta-analysis of prospective cohort studies.

BACKGROUND AND OBJECTIVES: Whether cigarette smoking can increase the risk of hip fracture in women is unclear. This meta-analysis, which pooled results from 10 prospective cohort studies, was performed to derive a more precise estimation between cigarette smoking and the risk of hip fracture in women. MATERIALS AND METHODS: Pubmed, Cochrane Central Register of Controlled Trials and ISI Web of Science were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association among 10 studies. The pooled risk estimates were calculated by using both random- and fixed-effects model. Heterogeneity among articles and their publications bias were also tested. All of the statistical analyses were performed using the software programs STATA (version 12.0). RESULTS: Relative risk was significantly increased in current female smokers (pooled RR, 1.30; 95%CI, 1.16-1.45). The association was significant among the high-dose smokers (more than 15 cigarettes per day) while not among the low-does smokers (less than 15 cigarettes per day). Omission of any single study had little effect on the pooled risk estimate. Former smokers had a similar RR of hip fracture (RR, 1.02; 95%CI, 0.93-1.11) to published papers. Smoking cessation for ≥10 years leads to a significant decline in risk. CONCLUSIONS: Smoking is associated with an increased hip fracture risk in women. Cessation of smoking for ≥10 years had a decreased impact on risk of hip fracture. Given the inconsistency among the studies in the choice of adjustments, the associations between cigarette smoking and risk of hip fracture in women await further investigation.

Local bone interaction between renin-angiotensin system and kallikrein-kinin system in diabetic rat.

OBJECTIVE: This study was performed to investigate bone deteriorations and the involvement of skeletal renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) of male rat in response to the hyperglycemia. METHODS: The biomarkers in serum and urine were measured by ELISA kit, and tibias were taken for the measurement on gene, protein expression and histological analysis, femurs were taken for the measurement on biomechanical parameters and micro-CT. RESULTS: The DM1 showed the decreased level of osteocalcin, testosterone and FGF-23, and the increased level of serum CTX as compared to those of vehicle group. The H&E staining showed remarkable bone deteriorations, including increased disconnections and separation of trabecular bone among growth plate and joint cartilage in DM1 group. Biomechanically, the maximum load, maximum stress, and strain parameter of DM1 group was significantly lower than control group. Type 1 diabetic mice displayed bone loss shown the reduction of bone volume/total volume, trabecular number, trabecular thickness and bone mineral density. The STZ injection significantly up-regulated mRNA expression of AT1R, AGT, renin, renin-receptor, and ACE, and the expression of AT2R, B1R and B2R were down-regulated in tibia of rat in hyperglycemia group. The protein expression of renin, ACE and Ang II were significantly up-regulated, and AT2R, B1R and B2R were down-regulated in DM1 group. CONCLUSIONS: The treatment of hyperglycemia was detrimental to bone as compared to the vehicle group, and the underlying mechanism was mediated, at least partially, through down-regulation of KSS activity and up-regulation of RAS activity in local bone.