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Weight regain after weight loss is a major challenge in the treatment of obesity. Immune cells adapt to fluctuating nutritional stress, but their roles in regulating weight regain remain unclear. Here, we identify a stem cell-like CD7+ monocyte subpopulation accumulating in the bone marrow (BM) of mice and humans that experienced dieting-induced weight loss. Adoptive transfer of CD7+ monocytes suppresses weight regain, whereas inducible depletion of CD7+ monocytes accelerates it. These cells, accumulating metabolic memories via epigenetic adaptations, preferentially migrate to the subcutaneous white adipose tissue (WAT), where they secrete fibrinogen-like protein 2 (FGL2) to activate the protein kinase A (PKA) signaling pathway and facilitate beige fat thermogenesis. Nevertheless, CD7+ monocytes gradually enter a quiescent state after weight loss, accompanied by increased susceptibility to weight regain. Notably, administration of FMS-like tyrosine kinase 3 ligand (FLT3L) remarkably rejuvenates CD7+ monocytes, thus ameliorating rapid weight regain. Together, our findings identify a unique bone marrow-derived metabolic-memory immune cell population that could be targeted to combat obesity. [Display omitted] • CD7+ monocytes accumulate in the bone marrow of mice and human after weight loss • Inducible depletion of CD7+ monocytes promotes robust weight regain • CD7+ monocytes infiltrate the iWAT and promote beige fat thermogensis via FGL2 • FLT3L stimulation rejuvenates resting CD7+ monocytes and constrains weight regain Weight regain after weight loss is a major challenge in obesity treatment. Zhou et al. identify a unique CD7+ monocyte population that accumulates in the bone marrow of mice and humans after weight loss. These immune cells are endowed with metabolic-memory capacities and enhance beige fat thermogenesis, thus constraining weight regain. [ABSTRACT FROM AUTHOR]

Exercise can prevent osteoporosis and improve immune function, but the mechanism remains unclear. Here, we show that exercise promotes reticulocalbin-2 secretion from the bone marrow macrophages to initiate bone marrow fat lipolysis. Given the crucial role of lipolysis in exercise-stimulated osteogenesis and lymphopoiesis, these findings suggest that reticulocalbin-2 is a pivotal regulator of a local adipose-osteogenic/immune axis. Mechanistically, reticulocalbin-2 binds to a functional receptor complex, which is composed of neuronilin-2 and integrin beta-1, to activate a cAMP-PKA signaling pathway that mobilizes bone marrow fat via lipolysis to fuel the differentiation and function of mesenchymal and hematopoietic stem cells. Notably, the administration of recombinant reticulocalbin-2 in tail-suspended and old mice remarkably decreases bone marrow fat accumulation and promotes osteogenesis and lymphopoiesis. These findings identify reticulocalbin-2 as a novel mechanosensitive lipolytic factor in maintaining energy homeostasis in bone resident cells, and it provides a promising target for skeletal and immune health. [Display omitted] • Macrophages secrete abundant RCN2 in response to mechanical stimulus • RCN2 initiates bone marrow fat lipolysis to fuel osteogenesis and lymphopoiesis • Rcn2 ablation impairs exercise-stimulated bone formation and immune response • Recombinant RCN2 treatment alleviates bone loss and improves immune function Peng et al. describe reticulocalbin-2 (RCN2) as a mechanosensitive lipolytic factor. RCN2 initiates lipolysis in bone marrow fat and supplies energy substrates to fuel osteogenesis and lymphopoiesis, thus resulting in a boost of bone mass and immune health. [ABSTRACT FROM AUTHOR]

Skeletal aging is characterized by low bone turnover and marrow fat accumulation. However, the underlying mechanism for this imbalance is unclear. Here, we show that during aging in rats and mice proinflammatory and senescent subtypes of immune cells, including macrophages and neutrophils, accumulate in the bone marrow and secrete abundant grancalcin. The injection of recombinant grancalcin into young mice was sufficient to induce premature skeletal aging. In contrast, genetic deletion of Gca in neutrophils and macrophages delayed skeletal aging. Mechanistically, we found that grancalcin binds to the plexin-b2 receptor and partially inactivates its downstream signaling pathways, thus repressing osteogenesis and promoting adipogenesis of bone marrow mesenchymal stromal cells. Heterozygous genetic deletion of Plexnb2 in skeletal stem cells abrogated the improved bone phenotype of Gca -knockout mice. Finally, we developed a grancalcin-neutralizing antibody and showed that its treatment of older mice improved bone health. Together, our data suggest that grancalcin could be a potential target for the treatment of age-related osteoporosis. [Display omitted] • In aging, senescent immune cells accumulate in the bone marrow and secrete grancalcin • Grancalcin represses osteogenesis and promotes adipogenesis via plexin-b2 in BMSCs • Genetic deletion of Gca in neutrophils and macrophages slows skeletal aging • Grancalcin-neutralizing antibody treatment improves skeletal health during aging Aging is marked by reduced osteogenesis and increased adipogenesis of bone marrow stromal cells, leading to bone fragility. Here, Li et al. show that senescent immune cells contribute to this process by accumulating in the bone marrow, where they secrete the protein grancalcin, which suppresses bone turnover and promotes marrow fat accumulation. [ABSTRACT FROM AUTHOR]

Osteoblasts rely on glucose as their primary energy source both for differentiation and to maintain function. Oxidative phosphorylation (OXPHOS) predominantly facilitates osteoclast differentiation, while glycolysis is the primary energy source for bone resorption by osteoclasts. Bone releases a series of endocrine factors to regulate systemic energy homeostasis. Disturbances in bone metabolism resulting from osteoporosis lead to imbalances in energy metabolism, further expediting the advance of osteoporosis. The bone serves as an energy reservoir and actively engages in whole-body energy metabolism. Numerous studies have determined fuel requirements and bioenergetic properties of bone under physiological conditions as well as the dysregulation of energy metabolism associated with bone metabolic diseases. Here, we review the main sources of energy in bone cells and their regulation, as well as the endocrine role of the bone in systemic energy homeostasis. Moreover, we discuss metabolic changes that occur as a result of osteoporosis. Exploration in this area will contribute to an enhanced comprehension of bone energy metabolism, presenting novel possibilities to address metabolic diseases. [ABSTRACT FROM AUTHOR]

Age-dependent loss of hypothalamic neural stem cells (htNSCs) is important for the pathological consequences of aging; however, it is unclear what drives the senescence of htNSCs. Here, we report that a long non-coding RNA, Hnscr , is abundantly expressed in the htNSCs of young mice but decreases markedly in middle-aged mice. We show that depletion of Hnscr is sufficient to drive the senescence of htNSCs and aging-like phenotypes in mice. Mechanistically, Hnscr binds to Y-box protein 1 (YB-1) to prevent its degradation and thus the attenuation of transcription of the senescence marker gene p16 INK4A . Through molecular docking, we discovered that a naturally occurring small compound, theaflavin 3-gallate, can mimic the activity of Hnscr. Treatment of middle-aged mice with theaflavin 3-gallate reduced the senescence of htNSCs while improving aging-associated pathology. These results point to a mediator of the aging process and one that can be pharmacologically targeted to improve aging-related outcomes. • The lncRNA Hnscr is highly expressed in htNSCs of young mice but decreases during aging • Hnscr depletion promotes the senescence of htNSCs and aging-like phenotypes • Hnscr attenuates htNSC senescence by binding to YB-1 to prevent its degradation • Theaflavin 3-gallate mimics Hnscr and ameliorates aging-related physiological disorders Loss of Hnscr is important for the senescence of hypothalamic stem cells via allowing YB-1 degradation and thus contributes to aging-related physiological decline. [ABSTRACT FROM AUTHOR]

Femoral neck geometric parameters (FNGPs) are closely related to the strength of the femoral neck and the risk of fragility fractures. No reference database is available for FNGPs for Chinese population, and gender-related differences in FNGPs as well as their association with the risk of femoral neck fractures are unknown. This investigation aimed to set up reference databases for FNGPs, understand gender-related differences in FNGPs, and examine the association between FNGPs and the risk of osteoporotic fractures of the femoral neck. This study included 5268 females and 2156 males (aged 15–91 years) from Chinese population. A total of 384 patients (282 females and 102 males) had sustained femoral neck fractures; 384 age- and sex-matched individuals without any fractures served as controls. Femoral neck DXA images were used to measure bone mineral density (BMD) and eight FNGPs. Our results showed that the age-related trends of FNGPs were fitted with the best goodness-of-fit by applying the cubic regression model. The trends shown by FNGPs were significantly different between male and female subjects, and the fitting curves were significantly higher in male subjects. After adjustments were made for age, height, weight, and body mass index, Cox regression analysis showed that changes in all FNGPs were related to increased hazard ratios (HRs) of femoral neck fractures. After further adjustment was made for BMD of the femoral neck, the HRs related to a cortical thickness (CT) decrease and buckling ratio (BR) increase in females went up by 3.35-folds (95% CI: 2.75–4.07) and 1.86-folds (95% CI: 1.33–2.60), respectively. In males, the HRs related to the decrease in CT and cross-sectional area (CSA) increased by 3.21-folds (95% CI: 2.32–4.45) and 1.88-folds (95% CI: 1.03–3.44), respectively. In conclusions, the reference databases of FNGPs established in this study will assist in the evaluation and prediction of femoral neck fracture risk in the clinic. The decrease in CT and increase in BR of the femoral neck were independent risk factors for osteoporotic fractures of the femoral neck in females from mainland China, while a decrease in CT and CSA were risk factors in male. [ABSTRACT FROM AUTHOR]

Abstract: Background: Cytokines including transforming growth factor beta 1 (TGF-β1) and osteoprotegerin (OPG) are closely related to bone metabolism. However, the relationships between TGF-β1, OPG and risk of osteoporosis in native Chinese women are unknown. Our research indicated that there is a positive correlation between TGF-β1 and bone mineral density (BMD) T-score, and a negative correlation between OPG and T-score. The risk of osteoporosis is reduced as TGF-β1 increases and increases as OPG was raised. We investigated correlations of BMD T-scores with circulating TGF-β1 and BMD T-scores with circulating OPG in healthy native Chinese women, and to study the effects of changes in TGF-β1 and OPG on osteoporosis. Methods: This was a cross-sectional study of 691 healthy native Chinese women aged 20–80years. Concentrations of serum TGF-β1 and OPG were determined. BMD T-scores at the posteroanterior spine, left hip, and forearm were measured by dual-energy X-ray absorptiometry. Results: There were positive correlations between serum TGF-β1 and T-scores at the various skeletal sites (r =0.167–0.285, all P =0.000) and negative correlations between serum OPG and T-scores (r =−0.179 to −0.270, all P =0.007–0.000). After adjusting for age and BMI, correlations between TGF-β1 and T-score at the lumbar vertebrae and ultradistal forearm, and between OPG and T-score at the ultradistal forearm in premenopausal subjects, remained statistically significant. Multivariate linear stepwise analysis showed that TGF-β1 could explain 1.9–8.3% of T-score variation at each skeletal site. OPG could explain 2.4–4.4% of T-score variation. When TGF-β1 and OPG concentrations were grouped according to quartile intervals, T-score and the prevalence and risk of osteoporosis varied with changes in the cytokines. Conclusions: The risk of osteoporosis in native Chinese women increased as circulating TGF-β1 was reduced and OPG was raised. [Copyright &y& Elsevier]

Abstract: Background: It remains unclear whether gonadotropins or estrogen is responsible for early bone mineral density (BMD) decrease in Chinese women. Methods: A cross-sectional study was conducted on 368 healthy adult women, aged 35–60years. We measured BMD, calculated BMD decrease rates (BDRs) and assessed serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) levels. Results: BDR was significantly negatively correlated with serum FSH (r =−0.429 to −0.622, all p =0.000) and LH (r =−0.359 to −0.526, all p =0.000). After adjustment for age and body mass index, the negative correlations of serum FSH and LH with BDR persisted, but there was no overall correlation between serum E2 and BDR. Multiple linear stepwise regression analysis suggested that serum FSH is a negative determinant of BDR. Serum E2 seems to be a positive determinant of BDR in a few parts of the skeleton. Conclusions: The decrease of BMD during the menopause is associated with FSH and LH levels, rather than E2 in Chinese women. [Copyright &y& Elsevier]

Abstract: Adiponectin may exert a negative effect on bone metabolism by regulating osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) expression. However, the action of adiponectin on bone may be influenced by estrogen in women. The present study was undertaken to investigate the effects of 17β-estradiol (E2) on adiponectin-regulated OPG and RANKL expression in human osteoblast. Human osteoblasts were treated with α-MEM containing 10μg/ml adiponectin alone or together with 10−10 to 10−8 M E2 for 12–48h. Cells were also treated with α-MEM containing 10μg/ml adiponectin together with 10−8 M E2 plus p38 agonist-anisomycin or estrogen receptor (ER) antagonist ICI182780 for 48h. The effects of E2 were also investigated by knockdown of ERs or overexpression of p38 MAPK in osteoblasts. Further, we examined the effects of E2 on adiponectin-dependent osteoclastogenesis by the co-culture systems of osteoblast and CD14+ peripheral blood monocytes (PBMCs). Real-time quantitative PCR (RT-PCR) and ELISA were used to detect OPG/RANKL mRNA and their corresponding protein expression, Western Blot was used to analyze the phosphorylated p38 (p-p38) levels. The results showed that E2 blocked adiponectin-induced p38 phosphorylation, decreased adiponectin-regulated OPG/RANKL mRNA and protein expression in a dose- and time-dependent manner. ICI182780 or knockdown of ERs abolished the effects of E2 on adiponectin-dependent p38 phosphorylation and OPG/RANKL expression. Furthermore, anisomycin or overexpression of p38 also reserved the effects of E2 on adiponectin-dependent p38 phosphorylation and OPG/RANKL expression. E2 inhibited adiponectin-dependent osteoclastogenesis in the co-culture systems of osteoblast and CD14+ PBMCs, whereas anisomycin, ICI182780, knockdown of ERs and overexpression of p38 significantly reversed this response. In conclusions, our findings demonstrated, through blocking the activation of adiponectin-induced p38 MAPK, E2 suppressed the adiponectin-regulated OPG/RANKL expression and then inhibited osteoclastogenesis, which suggested that estrogen would suppress the effect of adiponectin on bone metabolism. [Copyright &y& Elsevier]

Abstract: Background: Adiponectin and leptin, as the main circulating peptides secreted by adipose tissue, are potential contributors to bone metabolism. However, their association with bone mineral density (BMD) is unknown. We investigated whether these serum adipocytokines concentrations are associated with BMD and bone turnover markers. Methods: Serum adiponectin, leptin concentrations, bone turnover biochemical markers, and BMD were determined in 265 premenopausal and 336 postmenopausal Chinese women. Results: In postmenopausal Chinese women, the multiple linear stepwise regression analysis showed that year since menopause, lean mass, estradiol, and adiponectin, but not fat mass, leptin, were independent predictors of BMD in postmenopausal Chinese women. However, in premenopausal Chinese women, adiponectin was not the predictor of BMD. The significant positive correlations between adiponectin and bone-specific alkaline phosphatase (BAP), bone cross-linked N-telopeptides of type I collagen (NTX) were found only in postmenopausal women. Serum BAP, and NTX, but not adiponectin, decreased in response to alendronate therapy. Conclusions: Adiponectin was an independent predictor of BMD, and positively correlated with bone turnover biochemical markers in postmenopausal Chinese women, but not premenopausal women. It suggested that adiponectin may exert a negative effect on bone mass by promoting excessive bone resorption associated with bone loss. However, these effects may be mediated by menopausal status. [Copyright &y& Elsevier]

Abstract: WISP3 is essential for maintaining cartilage integrity mainly by regulating the expression of collagen II, and mutations of WISP3 linked to spondyloepiphyseal dysplasia tarda with progressive arthropathy (SEDT-PA) can compromise this function and lead to cartilage loss. The aim of this study was to evaluate the effect of WISP3 on insulin-like growth factor (IGF) signaling in human chondrocytes, investigate whether WISP3 up-regulates collagen II through the IGF signaling pathway, and compare IGF signaling between wild-type and mutant WISP3. Experimental results suggest that WISP3 up-regulates collagen II expression and inhibits the activation of IGF-IR, IRS-1, and ERK kinase in human chondrocytes, and mutation of WISP3 augments IGF signaling in human chondrocytes. In addition to the IGF signaling pathway, WISP3 might up-regulate collagen II expression through an IGF-independent signaling cascade. [Copyright &y& Elsevier]

Abstract: The aim of this study was to investigate the effects of apelin on proliferation and apoptosis of mouse osteoblastic MC3T3-E1 cells. APJ was expressed in MC3T3-E1 cells. Apelin did not affect Runx2 expression, alkaline phosphatase (ALP) activity, osteocalcin and type I collagen secretion, suggesting that it has no effect on osteoblastic differentiation of MC3T3-E1 cells. However, apelin stimulated MC3T3-E1 cell proliferation and inhibited cell apoptosis induced by serum deprivation. Our study also shows that apelin decreased cytochrome c release and caspase-3, capase-8 and caspase-9 activation in serum-deprived MC3T3-E1 cells. Apelin activated c-Jun N-terminal kinase (JNK) and Akt (phosphatidylinositol 3-kinase downstream effector), and the JNK inhibitor SP600125, the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 or the Akt inhibitor 1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate (HIMO) inhibited its effects on proliferation and serum deprivation-induced apoptosis. Furthermore, apelin protected against apoptosis induced by the glucocorticoid dexamethasone or TNF-α. Apelin stimulates proliferation and suppresses serum deprivation-induced apoptosis of MC3T3-E1 cells and these actions are mediated via JNK and PI3-K/Akt signaling pathways. [Copyright &y& Elsevier]

Abstract: Objectives: Apelin is a recently discovered peptide that is the endogenous ligand for the orphan G-protein-coupled receptor APJ. Adipocytes can express and secrete apelin. The aim of this study was to characterize apelin and APJ expression in human osteoblasts and to investigate the effects of apelin on osteoblasts. Results: Apelin and APJ were expressed in human osteoblasts. Apelin stimulated proliferation of human osteoblasts, but had no effect on alkaline phosphatase (ALP) activity, osteocalcin and type I collagen production in human osteoblasts. Suppression of APJ with small-interfering RNA (siRNA) abolished the apelin-induced cell proliferation. Apelin induced activation of Akt (Phosphatidylinositol-3 kinase downstream effector), but not MAPKs, such as c-jun N-terminal Kinase (JNK), p38 and ERK1/2 in human osteoblasts. This effect was blocked by suppression of APJ with siRNA. Furthermore, LY294002 (PI3 kinase inhibitor) blocked the activation of Akt by apelin and abolished the apelin-induced cell proliferation. Conclusions: Human osteoblasts express apelin and APJ and apelin enhances human osteoblast proliferation, but has no effect on osteoblast differentiation, and APJ/PI3 kinase/Akt pathway is involved in the proliferation response. These findings suggest that apelin may function as a mitogenic agent for osteoblasts. [Copyright &y& Elsevier]

Abstract: Background: Serum leptin concentration is associated with age, fat and bone mineral density (BMD), and there are ethnic differences in physique and BMD values. The relationship between serum leptin concentration and BMD in Chinese women is presently unknown. We examined the relationship of serum leptin concentration with age, body weight, BMI and BMD in mainland Chinese women. Methods: Serum leptin concentration in a population of 676 Chinese females, aged 20–80 years (45.4±14.8 years, mean±S.D.), was measured using an enzyme-linked immunosorbent assay (ELISA). BMD values were measured by dual-energy X-ray absorptiometry (DXA) at a number of sites: the posteroanterior lumbar spine (PA, L1–L4), lateral lumbar spine (Lat, L2–L4), hip (including the femoral neck (FN) and total hip (T-hip)), and forearm (one-third region (RU1/3) and total region (RUT)). The relationship between changes in serum leptin concentration with age, body weight, height, body mass index (BMI) and BMD values at six sites were analyzed using 10 different regression models, and the models giving the best fit were selected. Results: The cubic regression model best described the changes in serum leptin concentration with age (R2=0.048, p<0.001) and body weight (R2=0.352, p<0.001), while the quadratic regression model was best for serum leptin concentration changes with BMI (R2=0.410, p<0.001); serum leptin concentration was not correlated with height. Serum leptin concentration was significantly higher in postmenopausal than premenopausal women (p<0.001). Serum leptin concentration was correlated with Lat BMD (R2=0.012, p<0.018), FN BMD (R2=0.006, p<0.041) and T-hip BMD (R2=0.013, p<0.004) in the whole population. In premenopausal women, leptin was positively associated with BMD except for Lat (R2=0.029–0.055, p<0.008); in postmenopausal women, leptin was also positively associated with AP, FN, T-hip BMD (R2=0.026–0.042, p<0.007). However, after adjusting for BMI not for body weight, there was no association between serum leptin concentration and age. Meanwhile, after adjustment for age, body weight and BMI, there was no association between serum leptin concentration and BMD values in premenopausal and postmenopausal women. Conclusions: Age-related changes in serum leptin concentration is dependent on BMI, but not a direct determinant of BMD in Chinese females. [Copyright &y& Elsevier]