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Senescence and altered differentiation potential of bone marrow stromal cells (BMSCs) lead to age-related bone loss. As an important posttranscriptional regulatory pathway, alternative splicing (AS) regulates the diversity of gene expression and has been linked to induction of cellular senescence. However, the role of splicing factors in BMSCs during aging remains poorly defined. Herein, we found that the expression of the splicing factor Y-box binding protein 1 (YBX1) in BMSCs decreased with aging in mice and humans. YBX1 deficiency resulted in mis-splicing in genes linked to BMSC osteogenic differentiation and senescence, such as Fn1, Nrp2, Sirt2, Sp7, and Spp1, thus contributing to BMSC senescence and differentiation shift during aging. Deletion of Ybx1 in BMSCs accelerated bone loss in mice, while its overexpression stimulated bone formation. Finally, we identified a small compound, sciadopitysin, which attenuated the degradation of YBX1 and bone loss in old mice. Our study demonstrated that YBX1 governs cell fate of BMSCs via fine control of RNA splicing and provides a potential therapeutic target for age-related osteoporosis., (© 2023 The Authors.)

Autophagy is an evolutionarily conserved intracellular process and is considered one of the main catabolism pathways. In the process of autophagy, cells are digested nonselectively or selectively to recover nutrients and energy, so it is regarded as an antiaging process. In addition to the essential role of autophagy in cellular homeostasis, autophagy is a stress response mechanism for cell survival. Here, we review recent literature describing the pathway of autophagy and its role in different bone cell types, including osteoblasts, osteoclasts, and osteocytes. Also discussed is the mechanism of autophagy in bone diseases associated with bone homeostasis, including osteoporosis and Paget's disease. Finally, we discuss the application of autophagy regulators in bone diseases. This review aims to introduce autophagy, summarize the understanding of its relevance in bone physiology, and discuss its role and therapeutic potential in the pathogenesis of bone diseases such as osteoporosis., (© 2021 Wiley Periodicals LLC.)

A specific bone vessel subtype, strongly positive for CD31 and endomucin (CD31 hi Emcn hi ), is identified as coupling angiogenesis and osteogenesis. The abundance of type CD31 hi Emcn hi vessels decrease during ageing. Here we show that expression of the miR-497∼195 cluster is high in CD31 hi Emcn hi endothelium but gradually decreases during ageing. Mice with depletion of miR-497∼195 in endothelial cells show fewer CD31 hi Emcn hi vessels and lower bone mass. Conversely, transgenic overexpression of miR-497∼195 in murine endothelium alleviates age-related reduction of type CD31 hi Emcn hi vessels and bone loss. miR-497∼195 cluster maintains the endothelial Notch activity and HIF-1α stability via targeting F-box and WD-40 domain protein (Fbxw7) and Prolyl 4-hydroxylase possessing a transmembrane domain (P4HTM) respectively. Notably, endothelialium-specific activation of miR-195 by intravenous injection of aptamer-agomiR-195 stimulates CD31 hi Emcn hi vessel and bone formation in aged mice. Together, our study indicates that miR-497∼195 regulates angiogenesis coupled with osteogenesis and may represent a potential therapeutic target for age-related osteoporosis.

Bone marrow mesenchymal stem cells (BMSCs) exhibit an age-dependent reduction in osteogenesis that is accompanied by an increased propensity toward adipocyte differentiation. This switch increases adipocyte numbers and decreases the number of osteoblasts, contributing to age-related bone loss. Here, we found that the level of microRNA-188 (miR-188) is markedly higher in BMSCs from aged compared with young mice and humans. Compared with control mice, animals lacking miR-188 showed a substantial reduction of age-associated bone loss and fat accumulation in bone marrow. Conversely, mice with transgenic overexpression of miR-188 in osterix+ osteoprogenitors had greater age-associated bone loss and fat accumulation in bone marrow relative to WT mice. Moreover, using an aptamer delivery system, we found that BMSC-specific overexpression of miR-188 in mice reduced bone formation and increased bone marrow fat accumulation. We identified histone deacetylase 9 (HDAC9) and RPTOR-independent companion of MTOR complex 2 (RICTOR) as the direct targets of miR-188. Notably, BMSC-specific inhibition of miR-188 by intra-bone marrow injection of aptamer-antagomiR-188 increased bone formation and decreased bone marrow fat accumulation in aged mice. Together, our results indicate that miR-188 is a key regulator of the age-related switch between osteogenesis and adipogenesis of BMSCs and may represent a potential therapeutic target for age-related bone loss.

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 20-80 years. 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 © 2013 Elsevier B.V. All rights reserved.)

Aims: Omentin-1 (also known as intelectin-1) is a recently identified visceral adipose tissue-derived cytokine that is inversely related to obesity. Our previous study showed that omentin-1 inhibits osteoblastic differentiation of calcifying vascular smooth muscle cells (CVSMCs) in vitro. This study was undertaken to investigate the effects of omentin-1 on arterial calcification and bone metabolism in vivo., Methods and Results: In vitro, omentin-1 stimulated production of osteoprotegerin (OPG) and inhibited production of receptor activator for nuclear factor κB ligand (RANKL) in both CVSMCs and osteoblasts. In vivo, adenovirus-mediated over-expression of omentin-1 attenuated arterial calcification and bone loss in OPG(-/-) mice. All these in vitro and in vivo actions were abrogated by blockade of the PI3K-Akt signalling pathway. Furthermore, omentin-1 reduced serum levels of RANKL, tartarate-resistant acid phosphatase-5b and osteocalcin, all of which are increased dramatically in OPG(-/-) mice., Conclusion: These data suggest that omentin-1 ameliorates arterial calcification and bone loss in vivo through the regulation of the RANK signalling pathway.

MicroRNAs (miRNAs) interfere with translation of specific target mRNAs and are thought to thereby regulate many cellular processes. Recent studies have suggested that miRNAs might play a role in osteoblast differentiation and bone formation. Here, we identify a new miRNA (miR-2861) in primary mouse osteoblasts that promotes osteoblast differentiation by repressing histone deacetylase 5 (HDAC5) expression at the post-transcriptional level. miR-2861 was found to be transcribed in ST2 stromal cells during bone morphogenetic protein 2-induced (BMP2-induced) osteogenesis, and overexpression of miR-2861 enhanced BMP2-induced osteoblastogenesis, whereas inhibition of miR-2861 expression attenuated it. HDAC5, an enhancer of runt-related transcription factor 2 (Runx2) degradation, was confirmed to be a target of miR-2861. In vivo silencing of miR-2861 in mice reduced Runx2 protein expression, inhibited bone formation, and decreased bone mass. Importantly, miR-2861 was found to be conserved in humans, and a homozygous mutation in pre-miR-2861 that blocked expression of miR-2861 was shown to cause primary osteoporosis in 2 related adolescents. Consistent with the mouse data, HDAC5 levels were increased and Runx2 levels decreased in bone samples from the 2 affected individuals. Thus, our studies show that miR-2861 plays an important physiological role in osteoblast differentiation and contributes to osteoporosis via its effect on osteoblasts.

Background: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) may play an important role in bone mass regulation in postmenopausal women., Methods: A cross-sectional study of 699 healthy Chinese women, aged 20 to 82 y, was conducted. Serum FSH and LH and BMD were measured at the posteroanterior (PA) spine, lateral spine, total hip, and distal forearm., Results: The geometric mean values (+/-SD) of serum FSH and LH in premenopausal women were 3.94 +/- 2.08 and 7.51 +/- 2.58 IU/l, respectively, and in postmenopausal women were 28.8 +/- 1.88 and 25.6 +/- 1.95 IU/l, respectively. The correlation of FSH to BMD at different skeletal regions (r = -0.597 - -0.492, P = 0.000) was higher than that of LH to BMD (r = -0.452 - -0.332, P = 0.000). The prevalences of osteoporosis for the quartiles of FSH at various skeletal sites were 0.57%, 0.43%, 27.1%, and 30.9%, respectively; and of LH were 2.14%, 4.43%, 19.5%, and 26.0%, respectively. The prevalence of osteoporosis in 3rd and 4th quartile was more significantly increased than the 1st and 2nd quartile., Conclusions: These data suggest that FSH and LH levels in circulation are associated with BMD changes and osteoporosis occurrence in Chinese women.

Osteoporosis in men is an increasingly important public health problem. This study was designed to establish bone mineral density (BMD) reference databases for central southern Chinese men at multiple skeletal sites. We recruited 2433 native Chinese males for BMD assessment. Of these, 1537 were healthy volunteers (age range, 15-85 years), and 896 were suspected to have osteoporosis. BMD values were measured at the posteroanterior (PA) and lateral spine, hip, and distal forearm using a Delphi A absorptiometer. The quadratic regression model provided the best fit for age-related changes in BMD in the spine and hip. The cubic regression model was the best for describing age-related BMD changes in the distal forearm. Peak BMD in the lumbar spine, femoral neck, and total hip occurred at 15-19 years. Peak BMD at the distal forearm occurred at 40-44 years. The prevalence of primary osteoporosis in subjects ranging from 50-85 years was 4.3%-27.7% at various skeletal sites. Compared to the databases established here, the Hologic databases led to significantly higher osteoporosis detection rates. The BMD reference databases established for central southern Chinese men provide the most reliable diagnostic standards for osteoporosis detection in men of central south China.

Objective: To investigate prospectively the annual bone loss rate at spine, proximal femur and distal radius in females and its relationship to relevant factors., Methods: The bone mineral density (BMD) at anteroposterior lumber, proximal femur and distal radius in 220 women of Mawangdui Township, aged 36 - 60, was measured twice, March to April 2000 and March to April 2004, using a Hologic QDR 4500A fan beam X-ray bone densitometer., Results: The annual bone loss rate was the highest during the period of 1 to 5 years since menopause, showing an annual bone loss of 1.70% at the anteroposterior spine, and 2.21%, 1.92%, and 1.56% at the femoral neck, greater trochanter, and distal radius respectively. Even before menopause bone loss was found at the femoral neck and distal radius. BMD loss at the anteroposterior spine and greater trochanter was found in the peri-menopause group. The bone loss rate was the highest in the early menopause group (1.56%/year, P < 0.01), and became lower, however, not significantly in the late menopause group (0.38%/year, P > 0.05). Age was positively correlated with the annual bone loss rates at the anteroposterior spine, greater trochanter, and distal radius (gamma = 0.223 - 0.547, P < 0.05 - 0.01), and the number of year since menopause was also positively correlated with the annual bone loss rate at anteroposterior spine and greater trochanter (gamma = 0.432 - 0.569 P < 0.05 - 0.01). However, body weight and body mass index were negatively correlated with the annual bone loss rates at the anteroposterior spine, femoral neck, and greater trochanter (gamma = 0.239 - 0.466, P < 0.05 - 0.01)., Conclusion: Annual bone loss varies at different skeletal region. Age, years since menopause, and body weight influence the bone loss at different skeletal regions in females.

Objective: To investigate the effects of compound nylestriol tablet (CNT), containing nylestriol and levonorgestrel with a ratio of 1:0.3) and its components on the osteoporotic rat model induced by retinoic acid (RA) and ovariectomy (OVX)., Methods: We randomly divided 144 female SD rats (aged 7-month-old) into 12 groups (12 in each). In addition, 120 female SD rats aged 4-month were randomly divided into 10 groups (10 in each). Three dosage levels of CNT (0.039, 0.117 and 0.39 mg/kg body weight, daily), nylestriol (NYL, 0.30, 0.09 and 0.03 mg/kg body weight, daily) and levonorgestrel (LEV, 0.09, 0.027 and 0.009 mg/kg body weight, daily) were designed to prevent the bone loss of the osteoporotic rat model induced by RA and OVX respectively. Serum total calcium (Ca), phosphate (Pi), ALP, triglyceride (TG), total cholesterol (TC), HDL-C, total body BMD, isolated left femoral BMD and femoral Ca, and Pi after ashing were determined., Results: Osteoporotic models could be induced by RA (70 mg/kg body weightdaily given intragastrically for 14 days) or by ovariectomy; CNT and its components had the preventive effects on bone loss in both models; The preventive effect of CNT was dose-dependent and stronger than its components; Many observed markers showed us the levels of high and moderate CNT given to be the strongest, corresponding to an optimal choice of the moderate dose CNT about one tablet per week in adult women., Conclusions: CNT therapy can prevent the bone loss of RA-induced and OVX-induced osteoporotic rats, and its therapeutic and preventive effect is better than its components used alone.

Objective: Recently our studies have shown that nylestriol in combination with levonorgestrel prevented bone loss, decreased bone turnover rate and increased the maximal loading of bone without obvious side effects in retinoic acid (RA) induced osteoporotic rats. In addition to the animal experiments, we evaluate the effect of Compound Nylestriol Tablet (CNT) on bone mineral density (BMD) in women with postmenopausal osteoporosis. Compound Nylestriol Tablet, which contains 0.5 mg of nylestriol (cyclopentylethinyl estriol) and 0.15 mg of levonorgestrel per tablet, was authorized as a new anti-osteoporotic agent for clinical trial in postmenopausal osteoporosis., Methods: One year's clinical observation was performed in 191 eligible patients who were randomly divided into two groups (A and B). In group A, 119 patients were treated for one year with CNT (one tablet per week) and in group B, 72 patients with placebo. Bone mineral density of lumbar antero-posterior spine (L1-L4), lateral spine, total hip and total forearm positions including radius+ulna at the ultra distal areas, mid areas, and one-third areas, were measured before and after treatment. Biochemical parameters and effects of CNT on uterus, and breast were observed., Results: We found that patients treated with CNT had a significant decrease of bone loss in total forearm, including radius+ulna at the ultra distal, mid, and 1/3 areas compared with control subjects (all P < 0.05). An improved BMD tendency could be seen at the lumbar spine. There were no differences in the observed biochemical variables. No side-effects on uterus, or mammary glands observed. None of the patients had uterine bleeding or vertebral fractures during one year's CNT treatment., Conclusion: These data suggested that CNT is effective, safe and convenient in treating postmenopausal osteoporosis.

Objective: To determine an optimal dosage combination for a nylestriol/levonorgestrel (NYL/LNG) regimen in the treatment of female Sprague-Dawley (SD) rats with retinoic acid (RA)-induced osteoporosis in order to examine the rationale of NYL/LNG use for postmenopausal women., Methods: This study included two sets of experiments; one was designed to confirm the success of the RA-induced osteoporosis model involving 48 SD rats, and the other to determine the optimal dosage combination of NYL/LNG. In the second set of experiments, a total of 160 female SD rats at 7 months of age were randomly divided according to their basal body weights into 16 groups (10 in each). Treatment dosages of NYL and LNG were arrayed in a 2 factor-4 level (2(4)) factorial design, i.e., NYL level I (N1 0.015 mg/kg), level II (N(2) 0.05 mg/kg), level III (N3 0.15 mg/kg) and level IV (N4 0.5 mg/kg) and LNG level I (L1 0.005 mg/kg), level II (L2 0.015 mg/kg), level III (L3 0.05 mg/kg) and level IV (L4 0.15 mg/kg). For 14 d, 70 mg/kg/d RA was given intragastrically to establish the osteoporotic model and NYL and LNG were then administered in different dosages on alternate days over a 3 wk period. Subsequently, body weight, uterine weight, endometrial status, Bone mineral density (BMD), bone turnover, and morphometry as well as parameters of biomechanics, serum sex hormones and lipids and estrogen receptor-alpha expression were determined for these rats., Results: Uterine weights at L2, L3, and L4 dosage levels were significantly lower than those at L1 (P < 0.05). Serum estradiol at N4 and progesterone at N2, N3, and N4 had decreased. Bone mineral density at distal tibiae (R5) in L and LA, and at proximal femora (R3) in L4 had increased. The peak loading of lumbar vertebrae at N3 was higher than that at N1, N2, and N4 dosage levels and that of femora higher at N3 than that at N1 and N4. Serum alkaline phosphatase (ALP) levels at N3, N4, L2, L3, and L4 dosage levels were lower than those at N1, N2, and L1 (P < 0.05). Moreover, there were lower levels of trabecular separation (Tb.Sp) at N3 and N4. The mineral apposition rates (MAR) at N2, N3, N4, L2, L3, and L4 were lower than those at N1 or L1. Bone formation rates (BFR) at L3 and L4 had significantly decreased as compared with that at L1. Levels of serum total cholesterol (TC) at N2, N3, and N4 were lower than that at N1 (P < 0.05). Marked squamatization of uterine endometrium with an increased expression of estrogen receptor (ER)-alpha was observed at N4., Conclusion: The dosage of 0.15 mg/kg NYL prevented bone loss, decreased bone turnover rate and increased the maximal loading of bone without obvious side effects in RA-induced osteoporotic rats. The addition of 0.015-0.15 mg/kg of LNG (L2-L4) reduced uterine weights and serum ALP levels. Overall results showed that 0.15 mg/kg of NYL in combination with 0.015 mg/kg of LNG produced beneficial effects on bone metabolism in RA-induced osteoporotic rats.

This study was designed to establish Bone Mineral Density (BMD) Reference Databases for multiple skeletal sites appropriate for the diagnosis and evaluation of osteoporosis (OP) in Chinese women. We recruited 2702 healthy Chinese women, 5-96 years of age, for BMD assessment. BMD values at multiple skeletal sites including anteroposterior (AP) and lateral (Lat) lumbar spine, hip, and forearm were measured by dual-energy X-ray absorptiometry (DXA) using a QDR 4500A device; results were analyzed according to age group using eight regression models. BMD Reference Databases (CWD) were established according to the best regression equation and compared with Hologic reference databases for "Oriental Women" (OWD). Results indicated that the cubic regression model was superior to the quadratic, linear, logarithmic, and exponential regression models, etc. for our purpose, with a determinate coefficient ( R(2)) of 0.363-0.650 ( P = 0.000). We included 1636 female patients, aged 35-86 years, in our tests. In comparison with Hologic Reference Databases, the mean detection rate of OP in the newly established BMD Reference Databases for Chinese Women (CWD) was 16.0% +/- 2.68% lower (range, 13.7%-20.5%) at the AP spine, 16.8% +/- 11.0% lower (range, 3.5%-32.8%) at the Lat spine (except for L4), 18.7% +/- 4.6% lower (range, 12.6%-24.2%) at the hip, and 14.3% +/- 6.9% higher (range, 4.7%-24.3%) at the forearm. The difference in detection rates for OP was significant between the two reference databases ( P = 0.000), which was consistent with the differences in peak BMD values and the biological variability between them. Based upon our data, we confirmed that the Hologic BMD Reference Databases for Oriental Women (OWD) were not suitable for the diagnosis of OP in Chinese women; the BMD Reference Databases for Chinese Women (CWD) established in this study would provide reliable diagnostic standards for detection of OP in the women of South China.

ABSTRACT MicroRNAs (miRNAs) play important roles in osteoclastogenesis and bone resorption. However, no study has investigated the role of miRNA in postmenopausal osteoporosis. Here, we report that miR-503 was markedly reduced in circulating progenitors of osteoclasts-CD14+ peripheral blood mononuclear cells (PBMCs) from postmenopausal osteoporosis patients compared with those from postmenopausal healthy women. Overexpression of miR-503 in CD14+ PBMCs inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Conversely, silencing of miR-503 in CD14+ PBMCs promoted osteoclastogenesis. RANK, which is activated by the binding of RANKL and inducing osteoclast differentiation, was confirmed to be a target of miR-503. In vivo, silencing of miR-503 using a specific antagomir in ovariectomy (OVX) mice increased RANK protein expression, promoted bone resorption, and decreased bone mass, whereas overexpression of miR-503 with agomir inhibited bone resorption and prevented bone loss in OVX mice. Thus, our study revealed that miR-503 plays an important role in the pathogenesis of postmenopausal osteoporosis and contributes to a new therapeutic way for osteoporosis. © 2014 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) play crucial roles in bone metabolism. In the present study, we found that miR-148a is dramatically upregulated during osteoclastic differentiation of circulating CD14+ peripheral blood mononuclear cells (PBMCs) induced by macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). Overexpression of miR-148a in CD14+ PBMCs promoted osteoclastogenesis, whereas inhibition of miR-148a attenuated osteoclastogenesis. V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) is a transcription factor negatively regulating RANKL-induced osteoclastogenesis. miR-148a directly targeted MAFB mRNA by binding to the 3′ untranslated region (3′UTR) and repressed MAFB protein expression. In vivo, our study showed that silencing of miR-148a using a specific antagomir-inhibited bone resorption and increased bone mass in mice receiving ovariectomy (OVX) and in sham-operated control mice. Furthermore, our results showed that miR-148a levels significantly increased in CD14+ PBMCs from lupus patients and resulted in enhanced osteoclastogenesis, which contributed to the lower bone mineral density (BMD) in lupus patients compared with normal controls. Thus, our study provides a new insight into the roles of miRNAs in osteoclastogenesis, and contributes to a new therapeutic pathway for osteoporosis. © 2013 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]