Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells.

Background: Marrow adipose tissue (MAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the bone marrow (BM) niche. As a reflection of BM remodeling, MAT is highly responsive to nutrient fluctuations, hormonal changes, and metabolic disturbances such as obesity and diabetes mellitus. Expansion of MAT has also been strongly associated with bone loss in mice and humans. However, the regulation of BM plasticity remains poorly understood, as does the mechanism that links changes in marrow adiposity with bone remodeling. Methods: We studied deletion of Adipsin, and its downstream effector, C3, in C57BL/6 mice as well as the bone-protected PPARγ constitutive deacetylation 2KR mice to assess BM plasticity. The mice were challenged with thiazolidinedione treatment, calorie restriction, or aging to induce bone loss and MAT expansion. Analysis of bone mineral density and marrow adiposity was performed using a µCT scanner and by RNA analysis to assess adipocyte and osteoblast markers. For in vitro studies, primary bone marrow stromal cells were isolated and subjected to osteoblastogenic or adipogenic differentiation or chemical treatment followed by morphological and molecular analyses. Clinical data was obtained from samples of a previous clinical trial of fasting and high-calorie diet in healthy human volunteers. Results: We show that Adipsin is the most upregulated adipokine during MAT expansion in mice and humans in a PPARγ acetylation-dependent manner. Genetic ablation of Adipsin in mice specifically inhibited MAT expansion but not peripheral adipose depots, and improved bone mass during calorie restriction, thiazolidinedione treatment, and aging. These effects were mediated through its downstream effector, complement component C3, to prime common progenitor cells toward adipogenesis rather than osteoblastogenesis through inhibiting Wnt/ß-catenin signaling. Conclusions: Adipsin promotes new adipocyte formation and affects skeletal remodeling in the BM niche. Our study reveals a novel mechanism whereby the BM sustains its own plasticity through paracrine and endocrine actions of a unique adipokine. Funding: This work was supported by the National Institutes of Health T32DK007328 (NA), F31DK124926 (NA), R01DK121140 (JCL), R01AR068970 (BZ), R01AR071463 (BZ), R01DK112943 (LQ), R24DK092759 (CJR), and P01HL087123 (LQ).

Dietary predictors of the insulin-like growth factor system in adolescent females: results from the Dietary Intervention Study in Children (DISC).

BACKGROUND: The insulin-like growth factor (IGF) system is associated with the adult diet and chronic disease. Childhood diet may influence chronic disease through its effect on the IGF system; however, there is limited information describing the dietary predictors of the IGF system in adolescents. OBJECTIVE: We examined associations between dietary food intake [fat, protein (animal and vegetable), carbohydrate, lactose, dietary fiber, calcium, zinc, and sodium] and serum IGF-I, IGF binding protein 1 (IGFBP-1), IGF binding protein 3 (IGFBP-3), and the IGF-I:IGFBP-3 molar ratio in adolescent females. DESIGN: One hundred fifty-nine adolescent females in the Dietary Intervention Study in Children (age range: 14-18 y; 0.2-6.3 y postmenarche) were included. The dietary intake was assessed via three 24-h dietary recalls. IGF-related biomarkers were determined by using radioimmunoassays. Associations between dietary intakes and biomarkers were assessed with Pearson's correlations and multivariable linear regression. Dietary intakes and biomarkers were logarithmically transformed; thus, beta coefficients represented percentages. RESULTS: In analyses adjusted for energy, age, and time since menarche, significant correlations (P < 0.05) were as follows: IGF-I with total protein, lactose, calcium, and sodium; IGFBP-3 with total fat (inverse), lactose, fiber, and calcium; IGF-I/IGFBP-3 with lactose and calcium; and IGFBP-1 with vegetable protein. In multivariable analyses, significant predictors of IGF-I were energy (beta = 0.14, P < 0.05) and calcium (beta = 0.14, P < 0.01), the significant predictor of IGFBP-3 was calcium (beta = 0.07, P < 0.05), and significant predictors of IGFBP-1 were vegetable protein (beta = 0.49, P < 0.05) and body mass index-for-age percentile (beta = -0.01, P < 0.001). CONCLUSION: This study provides evidence that dietary intake affects IGF-related biomarkers-particularly elevated calcium with IGF-I and IGFBP-3 and elevated vegetable protein with IGFBP-1-and, to our knowledge, is novel in reporting these associations in adolescent females. The Dietary Intervention Study in Children was registered at clinicaltrials.gov as NCT00000459.

Evaluation of gene expression profiling in a mouse model of L-gulonolactone oxidase gene deficiency

Humans and guinea pigs are species which are unable to synthesize ascorbic acid (vitamin C) because, unlike rodents, they lack the enzyme L-gulonolactone oxidase (Gulo). Although the phenotype of lacking vitamin C in humans, named scurvy, has long been well known, information on the impact of lacking Gulo on the gene expression profiles of different tissues is still missing. This knowledge could improve our understanding of molecular pathways in which Gulo may be involved. Recently, we discovered a deletion that includes all 12 exons in the gene for Gulo in the sfx mouse, characterized by spontaneous bone fractures. We report here the initial analysis of the impact of the Gulo gene deletion on the murine gene expression profiles in the liver, femur and kidney.

Large-scale genome-wide linkage analysis for loci linked to BMD at different skeletal sites in extreme selected sibships.

UNLABELLED: Few genome-wide linkage studies of osteoporosis have been conducted in the Asian population. We performed a genome-wide scan involving 3093 adult siblings with at least one sib-pair extremely concordant or discordant for hip BMD. Our results indicated four genome-wide significant QTLs for BMD. In comparison with 12 previous reported linkage studies, we reveal novel linkage regions that have reaching global significance. INTRODUCTION: The genetic basis for osteoporosis has been firmly established, but efforts to identify genes associated with this complex trait have been incomplete, especially in Asian populations. The purpose of this study was to identify quantitative trait loci (QTLs) for BMD in a Chinese population. MATERIALS AND METHODS: We performed a genome-wide scan involving 3093 siblings 25-64 years of age from 941 families, with at least one sib-pair extreme concordant or discordant for total hip BMD from a large community-based cohort (n = 23,327) in Anhui, China. Linkage analysis was performed on BMD residuals adjusted for age, height, weight, occupation, cigarette smoking, physical activity, and alcohol consumption using the revised Haseman-Elston regression-based linkage model. RESULTS: Our results revealed significant QTLs on chromosome 7p21.2 for femoral neck BMD (LOD = 3.68) and on chromosome 2q24.3 for total hip BMD (LOD = 3.65). Suggestive linkage regions were found to overlap among different skeletal sites on chromosomes 2q, 7p, and 16q. Sex-specific linkage analysis further revealed a significant QTL for lumbar spine BMD on chromosome 13q21.1 (LOD = 3.62) in women only. When performing multivariate linkage analysis by combining BMDs at four skeletal sites (i.e., whole body, total hip, femoral neck, and lumbar spine BMD), an additional significant QTL was found at chromosome 5q21.2 (LOD = 4.56). None of these significant QTLs found in our study overlapped with major QTLs reported by other studies. CONCLUSIONS: This study reveals four novel QTLs in a Chinese population and suggests that BMD at different skeletal sites may also share common genetic determinants.

Evaluation of gene expression profiling in a mouse model of L-gulonolactone oxidase gene deficiency.

Humans and guinea pigs are species which are unable to synthesize ascorbic acid (vitamin C) because, unlike rodents, they lack the enzyme L-gulonolactone oxidase (Gulo). Although the phenotype of lacking vitamin C in humans, named scurvy, has long been well known, information on the impact of lacking Gulo on the gene expression profiles of different tissues is still missing. This knowledge could improve our understanding of molecular pathways in which Gulo may be involved. Recently, we discovered a deletion that includes all 12 exons in the gene for Gulo in the sfx mouse, characterized by spontaneous bone fractures. We report here the initial analysis of the impact of the Gulo gene deletion on the murine gene expression profiles in the liver, femur and kidney.

Relation of body composition, fat mass, and serum lipids to osteoporotic fractures and bone mineral density in Chinese men and women.

BACKGROUND: Higher fat mass may be an independent risk factor for osteoporosis and osteoporotic fractures. OBJECTIVE: We aimed to determine the independent contribution of fat mass to osteoporosis and to estimate the risk of osteoporotic fractures in relation to body weight, lean mass, and other confounders. DESIGN: This was a community-based, cross-sectional study of 7137 men, 4585 premenopausal women, and 2248 postmenopausal women aged 25-64 y. Total-body and hip bone mineral content (BMC) and bone mineral density (BMD) and body composition were measured by dual-energy X-ray absorptiometry. Serum lipids were measured. Sex- and menopause-specific multiple generalized linear models were applied. RESULTS: Across 5-kg strata of body weight, fat mass was significantly inversely associated with BMC in the whole body and total hip. When we compared the highest quartile with the lowest quartile of percentage fat mass in men, premenopausal women, and postmenopausal women, the adjusted odds ratios (95% CIs) of osteoporosis defined by hip BMD were 5.2 (2.1, 13.2), 5.0 (1.7, 15.1), and 6.9 (4.3, 11.2), respectively. Significant linear trends existed for higher risks of osteoporosis, osteopenia, and nonspine fractures with higher percentage fat mass. Significant negative relations were found between whole-body BMC and cholesterol, triacylglycerol, LDL, and the ratio of HDL to LDL in all groups. CONCLUSIONS: Risks of osteoporosis, osteopenia, and nonspine fractures were significantly higher for subjects with higher percentage body fat independent of body weight, physical activity, and age. Thus, fat mass has a negative effect on bone mass in contrast with the positive effect of weight-bearing itself.

Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men.

In order to assess the contribution of polymorphisms in the RANKL (TNFSF11), RANK (TNFRSF11A) and OPG (TNFRSF11B) genes to variations in bone mineral density (BMD), a population-based cohort with 1,120 extreme low hip BMD cases or extreme high hip BMD controls was genotyped on five SNPs. We further explored the associations between these genetic variations and forearm BMDs by genotyping 266 offspring and 309 available parents from 160 nuclear families. A family-based association test was used. Significantly positive associations were found for A163G polymorphisms in the promoter regions of the OPG gene, a missense substitution in exon 7 (Ala192Val) of the RANK gene and rs9594782 SNP in the 5' UTR of the RANKL gene with BMD in men only. Men with TC/CC genotypes of the rs9594782 SNP had a 2.1 times higher risk of extremely low hip BMD (P = 0.004), and lower whole body BMD (P < 0.001). Subjects with the TC genotype of the Ala192Val polymorphism had a 40% reduced risk of having extremely low hip BMD (P < 0.01), and higher whole body BMD (P < 0.01). Subjects with the GG genotype of the A163G polymorphism had a 70% reduced risk of having extremely low hip BMD (P < 0.05), and higher whole body BMD (P < 0.01). Significant gene-gene interactions were also observed among the OPG, RANK and RANKL genes. Our findings suggest that genetic variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are strongly associated with BMD at different skeletal sites in adult men, but not in women.