Regulation Of Bone Mineralization Research Articles

Association between high-density lipoprotein cholesterol and lumbar bone mineral density in Chinese: a large cross-sectional study

BackgroundThe association between lipid and bone metabolism, particularly the role of high-density lipoprotein cholesterol (HDL-C) in regulating bone mineral density (BMD), is of significant interest. Despite numerous studies, findings on this relationship remain inconclusive, especially since evidence from large, sexually diverse Chinese populations is sparse. This study, therefore, investigates the correlation between HDL-C and lumbar BMD in people of different genders using extensive population-based data from physical examinations conducted in China.MethodsData from a cross-sectional survey involving 20,351 individuals aged > = 20 years drawn from medical records of health check-ups at the Health Management Centre of the Henan Provincial People’s Hospital formed the basis of this study. The primary objective was to determine the correlation between HDL-C levels and lumbar BMD across genders. The analysis methodology included demographic data analysis, one-way ANOVA, subgroup analyses, multifactorial regression equations, smoothed curve fitting, and threshold and saturation effect analyses.ResultsMultifactorial regression analysis revealed a significant inverse relationship between HDL-C levels and lumbar BMD in both sexes, controlling for potential confounders (Male: β = -8.77, 95% CI -11.65 to -5.88, P < 0.001; Female: β = -4.77, 95% CI -8.63 to -0.90, P = 0.015). Subgroup and threshold saturation effect analyses indicated a stronger association in males, showing that increased HDL-C correlates with reduced lumbar BMD irrespective of age and body mass index (BMI). The most significant effect was observed in males with BMI > 28 kg/m2 and HDL-C > 1.45 mmol/L and in females with a BMI between 24 and 28 kg/m2.ConclusionElevated HDL-C is associated with decreased bone mass, particularly in obese males. These findings indicate that individuals with high HDL-C levels should receive careful clinical monitoring to mitigate osteoporosis risk.Trial registrationThe research protocol received ethics approval from the Ethics Committee at Beijing Jishuitan Hospital, in conformity with the Declaration of Helsinki guidelines (No. 2015-12-02). These data are a contribution of the China Health Quantitative CT Big Data Research team, registered at clinicaltrials.gov (code: NCT03699228).

Effect of magnesium deficiency on bone health

Objective. To assess the impact of magnesium deficiency on bone metabolism based on an analytical analysis of current literature, as well as to systematize data on the impact of magnesium deficiency on the development of osteoporosis, bone regeneration, and to consider it as a risk factor for fracture. Methods. The review is based on the analysis of literature sources from PubMed, Scopus, Web of Science, Cochrane Library, Google, Google Scholar, and RLNS. The search was conducted by keywords: magnesium, deficiency, magnesium and bone tissue, magnesium and osteoporosis, magnesium and fractures, magnesium and bone regeneration. Results. Magnesium is a key element in the metabolic and regulatory processes of the body. Its effects on bone tissue are direct and indirect. The direct magnesium effect on genes involved in osteogenesis is accompanied by proliferation of mesenchymal stem cells and osteoblasts, but magnesium deficiency leads to their reduction and apoptosis. In case of magnesium deficiency, the number and activity of osteoclasts increases. Magnesium regulates bone mineralization in a concentration-dependent manner. Magnesium deficiency increases bone resorption and affects osteopenia and osteoporosis, which can occur indirectly through decreased vitamin D levels, increased biosynthesis of parathyroid hormone, increased oxidative stress and biosynthesis of proinflammatory cytokines. However, data on bone mineral density at different skeletal sites in magnesium deficiency are ambiguous. Magnesium deficiency is considered a risk factor for fracture. It is of great importance for bone regeneration, affecting in various ways: it stimulates the proliferation and differentiation of mesenchymal stem cells and osteoblasts, periosteum cells, increases the movement of osteoblasts to the area of traumatic bone injury, and activates signaling pathways. At the early stage of regeneration magnesium has a positive effect on macrophages, its specificity of action is inhibition of transformation of M2 macrophages into M1 at the tissue-specific stage of regeneration. One of the mechanisms stimulating regeneration may be the effect of magnesium on axons, release and increase of calcitonin-related polypeptide α. Conclusions. Since hypomagnesemia is a potentially modifiable factor, this opens up prospects for maintaining bone health and requires further research in this area.

Mathematical model of physicochemical regulation of precipitation of bone hydroxyapatite

IntroductionFormation of hydroxyapatite in bone, dentin, and enamel occurs at restricted molecular sites of specific extracellular matrix proteins and is controlled by multiple mineralization inhibitors. However, the role of physicochemical factors, such as the availability of required ions and the saturation status of the aqueous environment in biological mineralization, is not fully understood. The goal of this study was to use mathematical modeling to describe the complex physicochemical environment permissive to the precipitation of biological hydroxyapatite.MethodsWe simulated the processes occurring in the bone interstitial fluid (ISF) defined as an aqueous environment containing seven chemical components (calcium, phosphate, carbonate, sodium, potassium, magnesium, and chloride) that form 30 chemical species. We simulated reversible equilibrium reactions among these chemical species, and calculated supersaturation for hydroxyapatite and its precipitation rate using kinetic theory.Results and DiscussionThe simulated ISF was of correct ionic strength and predicted the equilibrium component concentrations that were consistent with the experimental findings. Supersaturation of physiological ISF was ~15, which is consistent with prior findings that mineralization inhibitors are required to prevent spontaneous mineral precipitation. Only total calcium, total phosphate and to a lesser degree total carbonate affected ion availability, solution supersaturation and hydroxyapatite precipitation rate. Both calcium and phosphate levels directly affected hydroxyapatite precipitation, and phosphate was affected by pH, which additionally influenced hydroxyapatite precipitation. Integrating mathematical models capturing the physiochemical and biological factors regulating bone mineralization will allow in silico studies of complex clinical scenarios associated with alterations in ISF ion composition, such as rickets, hypophosphatemia, and chronic kidney disease.

Transcriptome changes during osteogenesis of porcine mesenchymal stem cells derived from different types of synovial membranes and genetic background

Synovial membrane mesenchymal stem cells (SMSCs) often serve as in vitro model for bone disease, but the molecular mechanisms driving osteogenesis in SMSCs from different donor cells of various sources and breeds remain unclear. In this study, porcine SMSCs isolated from adipose synovium (FP) and fibrous synovium (FS) of Angeln Saddleback (AS) and German Landrace (DL) were used to discover the signaling network change after osteogenic induction. During osteogenic differentiation, mineral deposition was first observed at day 14 and further increased until day 21. Transcriptional changes between day 1 and day 21 were enriched in several signaling pathways, including Wnt, PI3K-Akt, and TGF-beta pathway. Certain pathways related to osteogenesis, including osteoblast differentiation, regulation of bone mineralization, and BMP signaling pathway, were enriched at late time points, as confirmed by the osteogenic markers ALPL, COL1A1, and NANOG. A fraction of differentially expressed genes (DEGs) were found between FP and FS, while DEGs between AS and DL increased during the differentiation phase until day 7 and then decreased from day 14 to day 21. These genes are involved in several important signaling pathways, including TGF-beta, Wnt, and lipid-related signaling pathways, suggesting that SMSCs from these two breeds have different osteogenic capabilities.

Mechanical loading modulates phosphate related genes in rat bone.

Mechanical loading determines bone mass and bone structure, which involves many biochemical signal molecules. Of these molecules, Mepe and Fgf23 are involved in bone mineralization and phosphate homeostasis. Thus, we aimed to explore whether mechanical loading of bone affects factors of phosphate homeostasis. We studied the effect of mechanical loading of bone on the expression of Fgf23, Mepe, Dmp1, Phex, Cyp27b1, and Vdr. Twelve-week old female rats received a 4-point bending load on the right tibia, whereas control rats were not loaded. RT-qPCR was performed on tibia mRNA at 4, 5, 6, 7 or 8 hours after mechanical loading for detection of Mepe, Dmp1, Fgf23, Phex, Cyp27b1, and Vdr. Immunohistochemistry was performed to visualise FGF23 protein in tibiae. Serum FGF23, phosphate and calcium levels were measured in all rats. Four-point bending resulted in a reduction of tibia Fgf23 gene expression by 64% (p = 0.002) and a reduction of serum FGF23 by 30% (p<0.001), six hours after loading. Eight hours after loading, Dmp1 and Mepe gene expression increased by 151% (p = 0.007) and 100% (p = 0.007). Mechanical loading did not change Phex, Cyp27b1, and Vdr gene expression at any time-point. We conclude that mechanical loading appears to provoke both a paracrine as well as an endocrine response in bone by modulating factors that regulate bone mineralization and phosphate homeostasis.

Association of serum levels of Visfatin, Intelectin-1, RARRES2 and their genetic variants with bone mineral density in postmenopausal females.

Adipokines are engaged in bone physiology and regulate bone mineral density (BMD) by playing protective or cynical role in bone metabolism. The study is designed to measure and compare BMD, adipokines (retinoic acid receptor responder protein-2 RARRES2, visfatin and Intelectin-1) and their genetic variants in postmenopausal osteoporotic, osteopenic and non-osteoporotic females. This comparative study included postmenopausal non-osteoporotic (n=72), osteopenic (n=72) and osteoporotic (n=100) females with two years of amenorrhea and age between 50 to 70 years. Gold standard DXA was used to measure BMD. Hardy-Weinberg equilibrium was established. Kruskal-Wallis test for comparisons, logistic and multivariate regression analysis were used to rule out the predictors of BMD. On comparing the three groups, significant differences were observed in serum RARRES2 (p <0.001) and serum visfatin (p=0.050). The significant positive predictor of BMD at lumbar spine and total hip was serum visfatin. BMD at right and left femoral neck was predicted negatively by serum chemerin while BMD at left femoral neck was also predicted positively by serum calcium levels. There was significant difference in BMD at right femoral neck (p = 0.033) between rs7806429 genotypes. The odds of having low BMD increases with increasing serum levels of chemerin and decreasing serum levels of visfatin and calcium. The adipokines RARRES2 and visfatin are associated with BMD. RARRES2 is an independent negative and visfatin is positive predictor of BMD in postmenopausal females. BMD at right femoral neck was significantly low in RARRES2 rs7806429 TC heterozygotes.

Looking at Mountains: Role of Sustained Hypoxia in Regulating Bone Mineral Homeostasis in Relation to Wnt Pathway and Estrogen

Looking at Mountains: Role of Sustained Hypoxia in Regulating Bone Mineral Homeostasis in Relation to Wnt Pathway and Estrogen

Vitamin D and Forearm Fractures in Children Preliminary Findings: Risk Factors and Correlation between Low-Energy and High-Energy Fractures.

Background: The forearm is the most common fracture site in childhood, accounting for every fourth pediatric fracture. It is well described that vitamin D is involved in the regulation of bone mineralization and skeletal homeostasis by the regulation of calcium absorption. The aim of our study was to determine the influence of 25-hydroxyvitamin D levels on forearm fracture falls in a pediatric population, depending on level of energy impact. Additionally, we also aimed to evaluate the correlation between 25-hydroxyvitamin D levels and other tested risk factors for pediatric fractures. Methods: We evaluated 50 eligible children aged 3 to 12 years with a forearm fracture. According to energy impact, patients were grouped into low-energy fractures (LEF) and high-energy fractures (HEF) groups. The general characteristics of the patients included age, gender, sport participation, and fractured bone and its localization. We analyzed 25-hydroxyvitamin D, parathyroid hormone (PTH), calcium, magnesium, phosphate, C-reactive protein (CRP) levels, and body mass index (BMI). Results: There is a significant difference in the 25-hydroxyvitamin D levels distribution between LEF and HEF (p < 0.001) and PTH levels (p = 0.002). For magnesium levels, calcium levels, phosphate levels, and CRP levels, there were no significant differences in their frequency distribution. For the group of patients with LEF, there is a significantly positive correlation between 25-hydroxyvitamin D and calcium levels (p = 0.019) and a borderline significantly positive correlation between 25-hydroxyvitamin D and magnesium levels (p = 0.050). For the group of patients with HEF, there was only a significantly positive correlation between 25-hydroxyvitamin D and PTH levels (p < 0.001). Conclusions: Children with LEF were more frequently insufficient in 25-hydroxyvitamin D levels but had normal calcium levels, compared to the ones with HEF. These findings suggest that LEF and HEF in children might to a certain degree have different pathophysiological mechanisms.

The Interaction Between Intracellular Energy Metabolism and Signaling Pathways During Osteogenesis.

Osteoblasts primarily mediate bone formation, maintain bone structure, and regulate bone mineralization, which plays an important role in bone remodeling. In the past decades, the roles of cytokines, signaling proteins, and transcription factors in osteoblasts have been widely studied. However, whether the energy metabolism of cells can be regulated by these factors to affect the differentiation and functioning of osteoblasts has not been explored in depth. In addition, the signaling and energy metabolism pathways are not independent but closely connected. Although energy metabolism is mediated by signaling pathways, some intermediates of energy metabolism can participate in protein post-translational modification. The content of intermediates, such as acetyl coenzyme A (acetyl CoA) and uridine diphosphate N-acetylglucosamine (UDP-N-acetylglucosamine), determines the degree of acetylation and glycosylation in terms of the availability of energy-producing substrates. The utilization of intracellular metabolic resources and cell survival, proliferation, and differentiation are all related to the integration of metabolic and signaling pathways. In this paper, the interaction between the energy metabolism pathway and osteogenic signaling pathway in osteoblasts and bone marrow mesenchymal stem cells (BMSCs) will be discussed.

Zoledronic acid inhibits osteoclastogenesis and bone resorptive function by suppressing RANKL‑mediated NF‑κB and JNK and their downstream signalling pathways.

Targeting excessive osteoclast differentiation and activity is considered a valid therapeutic approach for osteoporosis. Zoledronic acid (ZOL) plays a pivotal role in regulating bone mineral density. However, the exact molecular mechanisms responsible for the inhibitory effects of ZOL on receptor activator of nuclear factor (NF)-κB ligand (RANKL)-induced osteoclast formation are not entirely clear. The present study aimed to investigate the role of ZOL in osteoclast differentiation and function, and to determine whether NF-κB and mitogen-activated protein kinase, and their downstream signalling pathways, are involved in this process. RAW264.7 cells were cultured with RANKL for differentiation into osteoclasts, in either the presence or absence of ZOL. Osteoclast formation was observed by tartrate-resistant acid phosphatase staining and bone resorption pit assays using dentine slices. The expression of osteoclast-specific molecules was analysed using reverse transcription-quantitative polymerase chain reaction and western blotting assays to deduce the molecular mechanisms underlying the role of ZOL in osteoclastogenesis. The results showed that ZOL significantly attenuated osteoclastogenesis and bone resorptive capacity in vitro. ZOL also suppressed the activation of NF-κB and the phosphorylation of c-Jun N-terminal kinase. Furthermore, it inhibited the expression of the downstream factors c-Jun, c-Fos and nuclear factor of activated T cells c1, thereby decreasing the expression of dendritic cell-specific transmembrane protein and other osteoclast-specific markers. In conclusion, ZOL may have therapeutic potential for osteoporosis.

Gene expression changes related to bone mineralization, blood pressure and lipid metabolism in mouse kidneys after space travel

Space travel burdens health by imposing considerable environmental stress associated with radioactivity and microgravity. In particular, gravity change predominantly impacts blood pressure and bone homeostasis, both of which are controlled mainly by the kidneys. Nuclear factor erythroid-2-related transcription factor 2 (Nrf2) plays essential roles in protecting the kidneys from various environmental stresses and injuries. To elucidate the effects of space travel on mammals in preparation for the upcoming space era, our study investigated the contribution of Nrf2 to kidney function in mice two days after their return from a 31-day stay in the International Space Station using Nrf2 knockout mice. Meaningfully, expression levels of genes regulating bone mineralization, blood pressure and lipid metabolism were found to be significantly altered in the kidneys after space travel in an Nrf2-independent manner. In particular, uridine diphosphate-glucuronosyltransferase 1A (Ugt1a) isoform genes were found to be expressed in an Nrf2-dependent manner and induced exclusively in the kidneys after return to Earth. Since spaceflight elevated the concentrations of fatty acids in the mouse plasma, we suggest that Ugt1a isoform expression in the kidneys was induced to promote glucuronidation of excessively accumulated lipids and excrete them into urine after the return from space. Thus, the kidneys were proven to play central roles in adaptation to gravity changes caused by going to and returning from space by controlling blood pressure and bone mineralization. Additionally, kidney Ugt1a isoform induction after space travel implies a significant role of the kidneys for space travelers in the excretion of excessive lipids.

PSV-6 Single nucleotide polymorphisms associated with advanced skeletal maturity in finished beef heifers

Abstract Accelerated skeletal maturity is prevalent in modern commercial heifers harvested under 30 months of age. It is hypothesized that selection for increased growth and earlier reproductive maturity over several decades, unintentionally co-selected for precocious skeletal ossification in heifers. This study examines the relationship of single nucleotide polymorphisms (SNPs) in beef heifers with developmental maturity (A-, B-, C- Maturity) assessed at harvest, and evaluates specific genotype and production implant potency interactions. Two SNPs within Estrogen Receptor 1 (ESR1) and one SNP within Alkaline Phosphatase (ALPL) genes that have been previously associated with carcass skeletal maturity were examined. USDA inspected beef heifer carcasses (&amp;lt; 30 months) that were A- (n = 318), B- (n = 296), or C- (n = 251) skeletal maturity were sampled. DNA was extracted and SNP genotypes were ascertained using custom designed allelic discrimination assays (Taqman® Custom SNP Assays). Dominant and basic association tests were performed, and the impact of implants were evaluated as co-variates against genotypes using a linear regression model in the SNP and Variation Suite (SVS) software (Golden Helix, Inc.). A significant association with skeletal maturity was detected with ESR1 SNP 1 (P &amp;lt; 0.05) and a trend observed with ALPL (P &amp;lt; 0.1), but there was no significance identified in ESR1 SNP 2. A highly significant interaction with genotype and incidence of skeletal maturity was identified for ESR1 SNP 1 (P &amp;lt; 0.01) and ALPL (P &amp;lt; 0.01) when estrogenic implant concentration was included. There exists a strong relationship for these genotypes and advanced skeletal maturity in commercial heifers which is influenced by estrogenic potency of the commercial implant used. This study confirms the association of previously identified genotypes with advanced skeletal maturity and provides evidence that genetic variations in ESR1 play an important role in the regulation of bone mineralization in heifers.

Effects of ERα gene overexpression on bone mineral density and calcium and phosphorus metabolism inovariectomized osteoporosis mice

Objective: To investigate the effects of estrogen receptor α (ERα) gene overexpression on bone metabolism and calcium and phosphorus metabolism in ovariectomized osteoporosis mice, and to provide experimental basis for targeted gene therapy of osteoporosis. Methods: Thirty SPF female mice were randomly divided into sham operation group, model group and ERα overexpression group with 10 mice in each group. After the model was established, the ERα overexpression group was transfected with recombinant adenovirus vector carrying mouse ERα gene by intraspinal injection. The model group was transfected with empty virus, and the sham operation group was not treated. The expression of ERα gene in bone tissue of mice was detected by quantitative Real-time PCR (qRT-PCR). Bone mineral density (BMD) of mouse femur was measured after modeling. Trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular segregation (Tb.Sp), bone volume fraction (BV/TV) and biomechanical strength of femur were measured by micro-CT scanning. Serum levels of calcium (Ca), phosphorus (P), osteocalcin (BGP) and alkaline phosphatase (ALP) were measured by automatic biochemical analyzer. The expressions of tissue inhibitor of metalloproteinases 1 (TIMP-1) and monocyte chemotactic protein 1 (MCP-1) in bone homogenate were detected by Immunohistochemistry. Results: Compared with sham operation group, the expression level of ERα gene in bone tissue of model group was decreased significantly, the levels of BMD, BV/TV, Tb. Th, maximum load, rigidity coefficient, Ca and P were decreased, while the levels of Tb. Sp, BGP and ALP were increased significantly (P＜0.05). Compared with the sham operation group, the expression level of TIMP-1 protein in the bone tissue of the model group was significantly decreased, while that of MCP-1 protein was increased, while that of the ERα overexpression group was increased while that of MCP-1 was decreased (P＜0.05).The levels of ERα gene expression, BMD, BV/TV, TB. Th, maximum load, rigidity coefficient, Ca and P in the ERα overexpression group were significantly higher than those in the model group, while Tb. Sp, BGP and ALP were significantly lower (P＜0.05). Compared with the sham operation group, mean optical density of TIMP-1 in the bone tissue of the model group was significantly decreased, while that of MCP-1 was significantly increased, and that of the ERα overexpression group was significantly increased while that of MCP-1 was significantly decreased (P＜0.05). Conclusion: ERα gene overexpression can improve osteoporosis by regulating bone mineral density, bone parameters, bone metabolism, calcium and phosphorus metabolic indicators and the expression levels of TIMP-1 and MCP-1 in tissues.

Cytoplasmic polyadenylation by TENT5A is required for proper bone formation.

Osteoblasts orchestrate bone formation through the secretion of type I collagen and other constituents of the matrix on which hydroxyapatite crystals mineralize. Here, we show that TENT5A, whose mutations were found in congenital bone disease osteogenesis imperfecta patients, is a cytoplasmic poly(A) polymerase playing a crucial role in regulating bone mineralization. Direct RNA sequencing revealed that TENT5A is induced during osteoblast differentiation and polyadenylates mRNAs encoding Col1α1, Col1α2, and other secreted proteins involved in osteogenesis, increasing their expression. We postulate that TENT5A, possibly together with its paralog TENT5C, is responsible for the wave of cytoplasmic polyadenylation of mRNAs encoding secreted proteins occurring during bone mineralization. Importantly, the Tent5a knockout (KO) mouse line displays bone fragility and skeletal hypomineralization phenotype resulting from quantitative and qualitative collagen defects. Thus, we report a biologically relevant posttranscriptional regulator of collagen production and, more generally, bone formation.

Sclerostin and Osteocalcin: Candidate Bone-Produced Hormones.

In addition to its structural role, the skeleton serves as an endocrine organ that controls mineral metabolism and energy homeostasis. Three major cell types in bone - osteoblasts, osteoclasts, and osteocytes – dynamically form and maintain bone and secrete factors with systemic activity. Osteocalcin, an osteoblast-derived factor initially described as a matrix protein that regulates bone mineralization, has been suggested to be an osteoblast-derived endocrine hormone that regulates multiple target organs including pancreas, liver, muscle, adipose, testes, and the central and peripheral nervous system. Sclerostin is predominantly produced by osteocytes, and is best known as a paracrine-acting regulator of WNT signaling and activity of osteoblasts and osteoclasts on bone surfaces. In addition to this important paracrine role for sclerostin within bone, sclerostin protein has been noted to act at a distance to regulate adipocytes, energy homeostasis, and mineral metabolism in the kidney. In this article, we aim to bring together evidence supporting an endocrine function for sclerostin and osteocalcin, and discuss recent controversies regarding the proposed role of osteocalcin outside of bone. We summarize the current state of knowledge on animal models and human physiology related to the multiple functions of these bone-derived factors. Finally, we highlight areas in which future research is expected to yield additional insights into the biology of osteocalcin and sclerostin.

Association Between Vitamin D and Resistin in Postmenopausal FemalesWith Altered Bone Health.

BackgroundResistin is a relatively novel adipokine that has a role in bone remodeling and may regulate bone mineral density (BMD). Vitamin D and adipokines have a dynamic role in the body’s various metabolic processes, including bone metabolism, and may alter bone metabolism in relation to each other. This study aimed to investigate the association between vitamin D and serum resistin levels in postmenopausal non-osteoporotic and osteoporotic females.MethodsThis correlational analytical study was conducted on 161 postmenopausal females, divided into two groups, non-osteoporotic and osteoporotic, between 50–70 years. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry (DXA) scan. Serum resistin and vitamin D levels were analyzed by enzyme-linked immunosorbent assay (ELISA) method. Serum calcium, phosphate, and alkaline phosphatase with spectrophotometry. A correlation was checked using spearman’s rho correlation coefficient, and multivariate stepwise regression analysis was used to predict serum resistin levels.ResultsPostmenopausal females (n=161) having sufficient, insufficient and deficient levels of vitamin D were 87 (54.0%), 64 (39.8%), and 10 (6.2%), respectively. Lumbar spine BMD (p < 0.001), total hip BMD (p < 0.001), and serum resistin levels (p < 0.001) were significantly different between the two groups. There was a significant negative correlation between serum resistin and vitamin D in postmenopausal females (rho = -0.182, p = 0.021) and osteoporotic group (rho = -0.253, p = 0.019) but non-significant in non-osteoporotic group (rho = -0.077, p = 0.509). Serum vitamin D was found to be independent predictor of serum resistin levels, accounting for only 3% variance.ConclusionSerum vitamin D levels were low while serum resistin levels were high in postmenopausal osteoporotic females and vitamin D is a negative predictor of serum resistin levels.

The Role of Vitamin D in Small Animal Bone Metabolism.

Dogs and cats have differences in vitamin D metabolism compared to other mammalian species, as they are unable to perform vitamin D cutaneous synthesis through sun exposure. Therefore, they are dependent on the dietary intake of this nutrient. The classic functions of vitamin D are to stimulate intestinal calcium and phosphate absorption, renal calcium and phosphate reabsorption and regulate bone mineral metabolism. Thus, it is an important nutrient for calcium and phosphorus homeostasis. This review highlights the evidence of the direct and indirect actions of vitamin D on bone mineral metabolism, the consequences of nutritional imbalances of this nutrient in small animals, as well as differences in vitamin D metabolism between different size dogs.

Sevelamer Use, Vitamin K Levels, Vascular Calcifications, and Vertebral Fractures in Hemodialysis Patients: Results from the VIKI Study

Hyperphosphatemia is a risk factor for vascular calcifications (VCs), which are part of the chronic kidney disease-mineral and bone disorders (CKD-MBD). Vitamin K-dependent proteins such as matrix Gla protein (MGP) and bone Gla proteins (BGP, or osteocalcin) can inhibit VCs and regulate bone mineralization. In this analysis of the Vitamin K Italian (VIKI) study, the relationship between vitamin K status, vertebral fractures (VFs) and VCs in 387 hemodialysis (HD) patients with (N = 163; 42.1%) or without N = 224; 57.9%) sevelamer was evaluated. Levels of vitamin K vitamers K1 and K2 or menaquinones (MK; MK4-7), total and undercarboxylated (uc) forms for both BGP and MGP were determined. Although no differences in clinical characteristics were noted, lower levels of MK4 (0.45 versus 0.6 ng/mL, p = .01) and a greater MK4 deficiency was observed in sevelamer-treated patients (13.5% versus 5.4%, p = .005). Multivariate logistic regression revealed that MK4 deficiency was associated with sevelamer use (odds ratio [OR] = 2.64, 95% confidence interval [CI] 1.25-5.58, p = .011) and aortic calcification (OR = 8.04, 95% CI 1.07-60.26, p = .04). In the same logistic model, sevelamer amplified the effect of total BGP levels on the odds of VFs in patients with total BGP <150 μg/L compared with those with total BGP ≥150 μg/L (OR = 3.15, 95% CI 1.46-6.76, p = .003). In contrast, there was no such effect in those untreated (total BGP <150 μg/L versus total BGP ≥150 μg/L: OR = 1.21, 95% CI 0.66-2.23, p = .54]; p = .049 for effect modification by sevelamer). Sevelamer may interfere with MK4 levels in HD patients and interact with low BGP levels to increase bone fractures in CKD patients. © 2020 American Society for Bone and Mineral Research (ASBMR).

Cytoplasmic Polyadenylation by TENT5A is Required for Proper Bone Formation

Osteoblasts orchestrate bone formation through the secretion of collagen type I and other constituents of the matrix on which hydroxyapatite crystals mineralize. Here we show that cytoplasmic poly(A) polymerase, TENT5A, whose mutations were found in osteogenesis imperfecta patients, plays a crucial role in regulating bone mineralization. Direct RNA sequencing revealed that TENT5A is induced during osteoblast differentiation and polyadenylates mRNAs encoding Col1α1, Col1α2, and other secreted proteins involved in osteogenesis, increasing their expression. We postulate that TENT5A is responsible for the wave of cytoplasmic polyadenylation of mRNAs encoding secreted proteins occurring during bone mineralization. Importantly, the TENT5A KO mouse line displays bone fragility and skeletal hypomineralization phenotype resulting from quantitative and qualitative collagen defects. Thus, for the first time, we report a biologically relevant posttranscriptional regulator of collagen production and, more generally, bone formation.

Comparative transcriptome analysis identifies CARM1 and DNMT3A as genes associated with osteoporosis

To identify new candidate genes in osteoporosis, mainly involved in epigenetic mechanisms, we compared whole gene-expression in osteoblasts (OBs) obtained from women undergoing hip replacement surgery due to fragility fracture and severe osteoarthritis. Then, we analyzed the association of several SNPs with BMD in 1028 women. Microarray analysis yielded 2542 differentially expressed transcripts belonging to 1798 annotated genes, of which 45.6% (819) were overexpressed, and 54.4% (979) underexpressed (fold-change between − 7.45 and 4.0). Among the most represented pathways indicated by transcriptome analysis were chondrocyte development, positive regulation of bone mineralization, BMP signaling pathway, skeletal system development and Wnt signaling pathway. In the translational stage we genotyped 4 SNPs in DOT1L, HEY2, CARM1 and DNMT3A genes. Raw data analyzed against inheritance patterns showed a statistically significant association between a SNP of DNMT3A and femoral neck-(FN) sBMD and primarily a SNP of CARM1 was correlated with both FN and lumbar spine-(LS) sBMD. Most of these associations remained statistically significant after adjusting for confounders. In analysis with anthropometric and clinical variables, the SNP of CARM1 unexpectedly revealed a close association with BMI (p = 0.000082), insulin (p = 0.000085), and HOMA-IR (p = 0.000078). In conclusion, SNPs of the DNMT3A and CARM1 genes are associated with BMD, in the latter case probably owing to a strong correlation with obesity and fasting insulin levels.