Loss Of Bone Mass Research Articles

Differential bone remodeling mechanism in hindlimb unloaded and hibernating Daurian ground squirrels: a comparison between artificial and natural disuse within the same species.

Loss of bone mass can occur in mammals after prolonged disuse but the situation for hibernators that are in a state of torpor for many months of the year is not yet fully understood. The present study assesses the bone remodeling mechanisms present in Daurian ground squirrels (Spermophilus dauricus) during hibernation as compared with a model of hindlimb disuse. Differences in microstructure, mechanical properties, bone remodeling-related proteins (Runx2, OCN, ALP, RANKL, CTK and MMP-9) and key proteins of Wnt/β-catenin signaling pathway (GSK-3β and phospho-β-catenin) were evaluated in ground squirrels under 3 conditions: summer active (SA) vs. hibernation (HIB) vs. hindlimb unloaded (HLU). The results indicated that the body weight in HLU ground squirrels was lower than the SA group, and the middle tibia diameter in the HLU group was lower than that in SA and HIB groups. The thickness of cortical and trabecular bone in femurs from HLU ground squirrels was lower than in SA and HIB groups. Most parameters of the tibia in the HLU group were lower than those in SA and HIB groups, which indicated cortical bone loss in ground squirrels. Moreover, our data showed that the changes in microscopic parameters in the femur were more obvious than those in the tibia in HLU and HIB ground squirrels. The levels of Runx2 and ALP were lower in HLU ground squirrels than SA and HIB groups. The protein levels of OCN were unchanged in the three groups, but the protein levels of ALP were lower in the HLU group than in SA and HIB groups. RANKL, CTK and MMP-9 protein levels were significantly decreased in tibia of HLU ground squirrels as compared with SA and HIB groups. In addition, the protein expression levels of RANKL, CTK and MMP-9 showed no statistical difference between SA and HIB ground squirrels. Thus, the mechanisms involved in the balance between bone formation and resorption in hibernating and hindlimb unloading ground squirrels may be different. The present study showed that in femur, the Wnt signaling pathway was inhibited, the protein level of GSK-3β was increased, and the protein expression of phospho-β-catenin was decreased in the HIB group as compared with the SA group, which indicates that the Wnt signaling pathway has a great influence on the femur of the HIB group. In conclusion, the natural anti-osteoporosis properties of Daurian ground squirrels are seasonal. The squirrels do not experience bone loss when they are inactive for a long time during hibernation, but the mechanisms of anti-osteoporosis did not work in HLU summer active squirrels.

Metformin reverses oxidative stress‑induced mitochondrial dysfunction in pre‑osteoblasts via the EGFR/GSK‑3β/calcium pathway.

Oxidative stress is one of the main causes of osteoblast apoptosis induced by post‑menopausal osteoporosis. The authors previously found that metformin can reverse the loss of bone mass in post‑menopausal osteoporosis. The present study aimed to further clarify the effects and mechanisms of action of metformin in post‑menopausal osteoporosis under conditions of oxidative stress. Combined with an in‑depth investigation using the transcriptome database, the association between oxidative stress and mitochondrial dysfunction in post‑menopausal osteoporosis was confirmed. A pre‑osteoblast model of oxidative stress was constructed, and the apoptotic rate following the addition of hydrogen peroxide and metformin was detected using CCK‑8 assay and Annexin V‑FITC/PI staining. Mitochondrial membrane potential was detected using the JC‑1 dye, the intracellular calcium concentration was detected using Fluo‑4 AM, the intracellular reactive oxygen species (ROS) level was observed using DCFH‑DA, and the mitochondrial superoxide level was observed using MitoSOX Red. Bay K8644 was used to increase the level of intracellular calcium. siRNA was used to interfere with the expression of glycogen synthase kinase (GSK)‑3β. Western blot analysis was used to detect the expression of mitochondrial dysfunction‑related proteins. The results revealed that oxidative stress decreased mitochondrial membrane potential and increased intracellular ROS, mitochondrial superoxide and cytoplasmic calcium levels in pre‑osteoblasts; however, metformin improved mitochondrial dysfunction and reversed oxidative stress‑induced injury. Metformin inhibited mitochondrial permeability transition pore opening, suppressed the cytoplasmic calcium influx and reversed pre‑osteoblast apoptosis by promoting GSK‑3β phosphorylation. Moreover, it was found that EGFR was the cell membrane receptor of metformin in pre‑osteoblasts, and the EGFR/GSK‑3β/calcium axis played a key role in metformin reversing the oxidative stress response of pre‑osteoblasts in post‑menopausal osteoporosis. On the whole, these findings provide a pharmacological basis for the use of metformin for the treatment of post‑menopausal osteoporosis.

Design, Synthesis, and Biological Evaluation of Androgen Receptor (AR) Antagonist-Heat Shock Protein 90 (Hsp90) Inhibitor Conjugates for Targeted Therapy of Castration-Resistant Prostate Cancer.

Androgen deprivation in cases of castration-resistant prostate cancer (CRPC) leads to adverse effects, including loss of muscle and bone mass and gain of subcutaneous fat. The tumor-specific suppression of androgen receptor (AR) signaling, while not global, may reduce side effects. We present a class of small-molecular conjugates consisting of an AR antagonist linked to a heat shock protein 90 (Hsp90) inhibitor. We demonstrate that the high accumulation of Hsp90 on the surface of CRPC cells allows uptake of conjugates and increases the enrichment of drugs in the tumor cells. After penetrating prostate cancer cells, the conjugates not only inhibit AR function by the antagonist component but also bind to Hsp90 and suppress the AR protein level. Compared to AR antagonists, these conjugates showed improved tumor-targeting ability and enhanced potency against Enzalutamide-resistant 22Rv1 cells.

Osoblyvosti stanu mineralnoi shchilnosty kistkovoi tkanyny u cholovikiv, khvorykh na ankilozyvnyi spondylit: chastota y kharakter porushen; vmist metabolichnykh pokaznykiv syntezu ta rezorbtsii kistkovoi tkanyny, vitaminu D v syrovattsi krovy; dostovirni chynnyky porushen

Introduction. Decreased bone mineral density (BMD) and the development of osteoporosis are common and poorly understood complications of ankylosing spondylitis (AS). Increased bone turnover and high inflammatory activity are important in the pathophysiology of AS-associated osteoporosis, and markers of bone remodeling are valuable markers for detecting bone loss The aim of the study. To find out the features of the BMD state in men with AS, based on establishing the frequency and nature of BMD violations, determining the content of metabolic indicators of bone tissue synthesis and resorption, vitamin D in blood serum, as well as identifying reliable factors involved in its violations. Materials and methods. The research group consisted of 83 men with AS, with an average age of 40.7 ± 0.8 years and a disease duration of 8.7 ± 0.5 years. Disease activity was determined by the BASDAI, ASDAS-CRB index. Laboratory examination included determination of C-reactive protein (CRP) and markers of bone tissue metabolism and vitamin D. BMD was measured using dual-energy X-ray absorptiometry Results. In men with AS, osteoporosis is found in 33.7 % of people, osteopenic syndrome in 28.9 % of patients, and normal indicators of BMD in 37.4 % of patients. We showed that low bone mass was closely related to the total indicators of the activity of the inflammatory process according to ASDAS, BASDAI and CRP content. In particular, in the group of patients with a very high degree of activity, the share of people with osteoporosis was equal to 78.6 %, and was 1.8 times higher than in the group of patients with moderate activity of AS. Similar patterns were observed for the BASDAI activity index and the pro-inflammatory marker CRP. In men with AS, the processes of bone resorption prevail over the processes of biosynthesis of bone tissue, as indicated by the preserved concentration of synthesis markers (OC, PINP) and the increase of the bone resorption marker (NTx) in blood serum. In addition, in the group of patients with osteoporosis, a high content of NTx was found in every second patient, and the average concentration was 39.0 % higher than in the group with preserved BMD. Loss of bone mass is closely related to a deficiency of vitamin D. Thus, in the group of patients with osteoporosis, in addition to probably low levels of vitamin D, a high proportion of people (57.2 %) with a severe deficiency was found, the insufficient level was in 43% and the optimal level equal to only 29.0 % of people. Conclusions. Patients with AS have a high frequency (62.6 %) of a decrease in BMD, while OP occurs in every third patient. Loss of bone mass depends on the activity of the inflammatory process, high levels of bone resorption markers and vitamin D deficiency.

N-acetyl-L-cysteine attenuates oxidative stress-induced bone marrow endothelial cells apoptosis by inhibiting BAX/caspase 3 pathway

Bone marrow endothelial cells (BMECs) play a crucial role in the maintenance of bone homeostasis. The decline in BMECs is associated with abnormal bone development and loss. At present, the mechanism of age-related oxidative stress enhancement in BMEC dysfunction remains unclear. Our experiment explored injury caused by oxidative stress enhancement in BMECs both in vivo and in vitro. The BMECs, indicators of oxidative stress, bone mass, and apoptosis-related proteins were analyzed in different age groups. We also evaluated the ability of N-Acetyl-L-cysteine (NAC) attenuate oxidative stress injury in BMECs. NAC treatment attenuated reactive oxygen species (ROS) overgeneration and apoptosis in BMECs in vitro and alleviated the loss of BMECs and bone mass in vivo. In conclusion, this study could improve our understanding of the mechanism of oxidative stress-induced BMECs injury and whether NAC has therapeutic potential in senile osteoporosis.

Recombinant irisin prevents cell death and mineralization defects induced by random positioning machine exposure in primary cultures of human osteoblasts: A promising strategy for the osteoporosis treatment.

Spaceflight exposure, like prolonged skeletal unloading, is known to result in significant bone loss, but the molecular mechanisms responsible are still partly unknown. This impairment, characterizing both conditions, suggests the possibility of identifying common signalling pathways and developing innovative treatment strategies to counteract the bone loss typical of astronauts and osteoporotic patients. In this context, primary cell cultures of human osteoblasts derived from healthy subjects and osteoporotic patients were exposed to random positioning machine (RPM) to reproduce the absence of gravity and to exacerbate the pathological condition, respectively. The duration of exposure to RPM was 3 or 6days, with the aim of determining whether a single administration of recombinant irisin (r-irisin) could prevent cell death and mineralizing capacity loss. In detail, cellular responses were assessed both in terms of death/survival, by MTS assay, analysis of oxidative stress and caspase activity, as well as the expression of survival and cell death proteins, and in terms of mineralizing capacity, by investigating the pentraxin 3 (PTX3) expression. Our results suggest that the effects of a single dose of r-irisin are maintained for a limited time, as demonstrated by complete protection after 3days of RPM exposure and only partial protection when RPM exposure was for a longer time. Therefore, the use of r-irisin could be a valid strategy to counteract the bone mass loss induced by weightlessness and osteoporosis. Further studies are needed to determine an optimal treatment strategy based on the use of r-irisin that is fully protective even over very long periods of exposure and/or to identify further approaches to be used in a complementary manner.

Isoimperatorin attenuates bone loss by inhibiting the binding of RANKL to RANK

Osteoporosis, an immune disease characterized by bone mass loss and microstructure destruction, is often seen in postmenopausal women. Isoimperatorin (ISO), a bioactive, natural furanocoumarin isolated from many traditional Chinese herbal medicines, has therapeutic effects against various diseases; however, its effect on bone homeostasis remains unclear. In this study, we investigated the effect of ISO on the differentiation and activation of osteoclast and its molecular mechanism in vitro, and evaluated the effect of ISO on bone metabolism by ovariectomized (OVX) rat model. In vitro experiments showed that ISO affected RANKL-induced MAPK, NFAT, NFATc1 trafficking and expression, osteoclast F-actin banding, osteoclast-characteristic gene expression, ROS inhibitory activity, and calcium oscillations, NF-κB signaling pathway. In vivo experiments showed that oral administration of ISO effectively reduced bone loss caused by ovariectomy and retained bone mass.Collectively, ISO inhibits RANK/RANKL binding, thereby reducing the activity of NFATc1, calcium, and ROS and inhibiting osteoclast generation. In addition, ISO protects bone mass by slowing osteoclast production and downregulating NFATc1 gene and protein expression in the bone tissue microenvironment and inhibits OVX-induced bone loss in vivo.

Progress of Wnt Signaling Pathway in Osteoporosis

Osteoporosis, one of the serious health diseases, involves bone mass loss, bone density diminishing, and degeneration of bone microstructure, which is accompanied by a tendency toward bone fragility and a predisposition to fracture. More than 200 million people worldwide suffer from osteoporosis, and the cost of treating osteoporotic fractures is expected to reach at least $25 billion by 2025. The generation and development of osteoporosis are regulated by genetic factors and regulatory factors such as TGF-β, BMP, and FGF through multiple pathways, including the Wnt signaling pathway, the Notch signaling pathway, and the MAPK signaling pathway. Among them, the Wnt signaling pathway is one of the most important pathways. It is not only involved in bone development and metabolism but also in the differentiation and proliferation of chondrocytes, mesenchymal stem cells, osteoclasts, and osteoblasts. Dkk-1 and SOST are Wnt inhibitory proteins that can inhibit the activation of the canonical Wnt signaling pathway and block the proliferation and differentiation of osteoblasts. Therefore, they may serve as potential targets for the treatment of osteoporosis. In this review, we analyzed the mechanisms of Wnt proteins, β-catenin, and signaling molecules in the process of signal transduction and summarized the relationship between the Wnt signaling pathway and bone-related cells. We hope to attract attention to the role of the Wnt signaling pathway in osteoporosis and offer new perspectives and approaches to making a diagnosis and giving treatment for osteoporosis.

UPLC/Q-TOF-MS-based metabolomics evaluate the efficacy of oroxylin A against postmenopausal osteoporosis.

Post-menopausal osteoporosis (PMOP) is a common metabolic bone malady characterized by bone mass loss and bone microarchitectural deterioration; however, there is currently no effective drug for its management. According to our previous study, oroxylin A (OA) could effectively protect ovariectomized (OVX)-osteoporotic mice from bone loss; however, its therapeutic targets are still unclear. From a metabolomic perspective, we studied serum metabolic profiles to discover potential biomarkers and OVX-related metabolic networks, which could assist us to comprehend the impact of OA on OVX. Five metabolites were identified as biomarkers associated with 10 related metabolic pathways, including phenylalanine, tyrosine and tryptophan biosynthesis, and phenylalanine, tryptophan and glycerophospholipid metabolism. After OA treatment, the expression of multiple biomarkers changed, with lysophosphatidylcholine (18:2) being a major significantly regulated biomarker. Our study demonstrated that OA's effects on OVX are probably related to the regulation of phenylalanine, tyrosine and tryptophan biosynthesis. Our findings explain the role of OA against PMOP in terms of metabolism and pharmacology and provide a pharmacological foundation for OA treatment of PMOP.

Risk Genetic Variants (IL-10) for Osteoporosis in Han Population from Northwest China.

Osteoporosis (OP) is a common metabolic bone disease characterized by loss of bone mass. IL-10 is considered to be a powerful immune and inflammatory suppressor. This study aimed to assess association between genetic loci in IL-10 and susceptibility to OP. Association analysis between IL-10 genetic loci and OP risk through SNPStats online software. FPRP analysis (false-positive report probability) verified whether the positive results were noteworthy findings. Linkage disequilibrium (LD) and haplotype analysis were completed by Haploview 4.2 and SNPStats. Multi-factor dimensionality reduction (MDR) was used to assess interaction of SNP-SNP in susceptibility to OP. Allele "G" of IL-10-rs1554286 (OR = 1.21, p = 0.013), allele "C" of IL-10-rs1518111 (OR = 1.22, p = 0.011), allele "C" of IL-10-rs3024490 (OR = 1.20, p = 0.018), and allele "G" of IL-10-rs1800871 (OR = 1.21, p = 0.015) were risk factors for OP. In females, smoking, drinking, or aging ≤60 years old participants, the above genetic loci are also significantly associated with the increased risk of OP. FPRP analysis showed that all positive results are noteworthy findings. There are significant differences in serum levels of uric acid, mean hemoglobin concentration, or mean hemoglobin among different genotypes of IL-10 gene loci. MDR showed that four loci model composed rs1554286, rs1518111, rs3021094, and rs1800871 is the best model for predicting OP risk. IL-10-rs1554286, -rs1518111, -rs3021094, and -rs1800871 are risk factors for susceptibility to OP.

VK2 promotes osteogenic differentiation of BMSCs against high glucose exposure via modulation of intracellular oxidative stress.

Diabetic osteoporosis (DOP) has gradually gained public attention. The clinical manifestations of DOP include bone mass loss, bone microstructural damage, and increased bone fragility. Intracellular reactive oxygen species (ROS) production was significantly increased under high glucose (HG) conditions, with deleterious effects on bone mesenchymal stem cells (BMSCs) proliferation and osteogenic differentiation. Vitamin K2 (VK2) has been demonstrated to promote bone formation both in vitro and in vivo. However, its potential role in diabetes-induced osteoporosis remains unelucidated. This study aims to verify whether VK2 treatment could relieve the deleterious effects of high glucose on BMSCs and delay the progression of osteoporosis. The results revealed that the HG environment downregulated the expression of osteogenesis-related proteins. Correspondingly, VK2 treatment reversed the osteogenic phenotype of BMSCs under HG conditions. In addition, using an established diabetes-induced osteoporosis rat model, we found that VK2 administration could restore bone mass and microstructure. In conclusion, our results provide a promising therapeutic option in the clinical treatment of DOP.

A standardized extract of Coleus forskohlii root protects rats from ovariectomy-induced loss of bone mass and strength, and impaired bone material by osteogenic and anti-resorptive mechanisms.

In obese humans, Coleus forskohlii root extract (CF) protects against weight gain owing to the presence of forskolin, an adenylate cyclase (AC) activator. As AC increases intracellular cyclic adenosine monophosphate (cAMP) levels in osteoblasts that has an osteogenic effect, we thus tested the skeletal effects of a standardized CF (CFE) in rats. Concentrations of forskolin and isoforskolin were measured in CFE by HPLC. CFE and forskolin (the most abundant compound present in CFE) were studied for their osteogenic efficacy in vitro by alkaline phosphatase (ALP), cAMP and cyclic guanosine monophosphate (cGMP) assays. Femur osteotomy model was used to determine the osteogenic dose of CFE. In growing rats, CFE was tested for its osteogenic effect in intact bone. In adult ovariectomized (OVX) rats, we assessed the effect of CFE on bone mass, strength and material. The effect of forskolin was assessed in vivo by measuring the expression of osteogenic genes in the calvarium of rat pups. Forskolin content in CFE was 20.969%. CFE increased osteoblast differentiation and intracellular cAMP and cGMP levels in rat calvarial osteoblasts. At 25 mg/kg (half of human equivalent dose), CFE significantly enhanced calcein deposition at the osteotomy site. In growing rats, CFE promoted modeling-directed bone formation. In OVX rats, CFE maintained bone mass and microarchitecture to the level of sham-operated rats. Moreover, surface-referent bone formation in CFE treated rats was significantly increased over the OVX group and was comparable with the sham group. CFE also increased the pro-collagen type-I N-terminal propeptide: cross-linked C-telopeptide of type-I collagen (PINP : CTX-1) ratio over the OVX rats, and maintained it to the sham level. CFE treatment decreased the OVX-induced increases in the carbonate-to-phosphate, and carbonate-to-amide-I ratios. CFE also prevented the OVX-mediated decrease in mineral crystallinity. Nanoindentation parameters, including modulus and hardness, were decreased by OVX but CFE maintained these to the sham levels. Forskolin stimulated ALP, cAMP and cGMP in vitro and upregulated osteogenic genes in vivo. CFE, likely due to the presence of forskolin displayed a bone-conserving effect via osteogenic and anti-resorptive mechanisms resulting in the maintenance of bone mass, microarchitecture, material, and strength.

MiR-422a promotes adipogenesis via MeCP2 downregulation in human bone marrow mesenchymal stem cells

Methyl-CpG binding protein 2 (MeCP2) is a ubiquitous transcriptional regulator. The study of this protein has been mainly focused on the central nervous system because alterations of its expression are associated with neurological disorders such as Rett syndrome. However, young patients with Rett syndrome also suffer from osteoporosis, suggesting a role of MeCP2 in the differentiation of human bone marrow mesenchymal stromal cells (hBMSCs), the precursors of osteoblasts and adipocytes. Here, we report an in vitro downregulation of MeCP2 in hBMSCs undergoing adipogenic differentiation (AD) and in adipocytes of human and rat bone marrow tissue samples. This modulation does not depend on MeCP2 DNA methylation nor on mRNA levels but on differentially expressed miRNAs during AD. MiRNA profiling revealed that miR-422a and miR-483-5p are upregulated in hBMSC-derived adipocytes compared to their precursors. MiR-483-5p, but not miR-422a, is also up-regulated in hBMSC-derived osteoblasts, suggesting a specific role of the latter in the adipogenic process. Experimental modulation of intracellular levels of miR-422a and miR-483-5p affected MeCP2 expression through direct interaction with its 3′ UTR elements, and the adipogenic process. Accordingly, the knockdown of MeCP2 in hBMSCs through MeCP2-targeting shRNA lentiviral vectors increased the levels of adipogenesis-related genes. Finally, since adipocytes released a higher amount of miR-422a in culture medium compared to hBMSCs we analyzed the levels of circulating miR-422a in patients with osteoporosis—a condition characterized by increased marrow adiposity—demonstrating that its levels are negatively correlated with T- and Z-scores. Overall, our findings suggest that miR-422a has a role in hBMSC adipogenesis by downregulating MeCP2 and its circulating levels are associated with bone mass loss in primary osteoporosis.

Evaluation of Metabolic Parameters on Use of Newer Antiepileptics Versus Conventional Antiepileptics in Patients of Generalised Tonic-Clonic Seizure: An Observational Study.

Background and objective Epilepsy is the commonest serious neurological condition and around 50 million people live with epilepsy (PWE). Primary and secondary generalised tonic-clonic seizures (GTCS) together constitute up to 50% of adult and adolescent epilepsy. GTCS respond well to broad-spectrum AEDs like valproate, phenytoin, levetiracetam, lamotrigine, and topiramate. Carbamazepine and oxcarbazepine are considered alternatives. Metabolic derangements with the conventional AEDs (phenytoin causes loss of bone mass in women, phenytoin and carbamazepine produce increases in serum lipid and C-reactive protein, weight gain with valproate) are well documented. But, there is limited data regarding the effect of the newer AEDs on metabolic parameters. Thus, this study was undertaken to assess the effects of the newer AEDs on the metabolic profile of patients with epilepsy. Material and methods A prospective observational study was conducted in the Department of Pharmacology, in collaboration with the Department of Neurology at S.C.B. Medical College and Hospital, Cuttack. 100 diagnosed patients with GTCS receiving monotherapy of either conventional or newer anti-epileptics were included in the study. Their metabolic parameters like total cholesterol, serum sodium, serum TSH and fasting blood glucose were collected at baseline, three months, and six months. ADRs were collected during the entire study period and causality assessment was done using WHO-UMC Causality Assessment Scale. All the data were analysed using SPSS 20.0 after applying appropriate statistical tests. Results There was a significant increase in total cholesterol in all four groups (p=0.002) but a pathological increasein the phenytoin and oxcarbazepine groups. There was a significant rise in the serum TSH levels in all groups except levetiracetam, but a pathological increase was seen with phenytoin and valproate, i.e., the conventional ones. Statistically significant hyponatremia was seen with valproate and oxcarbazepine. A rise in the FBS was seen with both phenytoin and valproate (p=0.002) but a pathological rise was seen with phenytoin. Out of the total reported ADRs, 53.5% were seen with conventional AEDs, and the rest 46.5% were seen with newer ones. Conclusion The advent of newer anti-epileptic drugs has unfolded wider horizons to the treatment of epilepsy. Each of these drugs has a unique mechanism of action, making it less prone to resistance. Metabolic derangements are a key determinant in the compliance of these drugs as they can predispose to other co-morbidities. Periodic monitoring of the various metabolic parameters is useful and together with patient counselling can improve the effectiveness of the anti-epileptic drugs.

Bone and Cytokine Markers Associated With Bone Disease in Systemic Mastocytosis

Mastocytosis encompasses a heterogeneous group of diseases characterized by tissue accumulation of clonal mast cells, which frequently includes bone involvement. Several cytokines have been shown to play a role in the pathogenesis of bone mass loss in systemic mastocytosis (SM), but their role in SM-associated osteosclerosis remains unknown. To investigate the potential association between cytokine and bone remodeling markers with bone disease in SM, aiming at identifying biomarker profiles associated with bone loss and/or osteosclerosis. A total of 120 adult patients with SM, divided into 3 age and sex-matched groups according to their bone status were studied: (1) healthy bone (n= 46), (2) significant bone loss (n= 47), and (3) diffuse bone sclerosis (n= 27). Plasma levels of cytokines and serum baseline tryptase and bone turnover marker levels were measured at diagnosis. Bone loss was associated with significantly higher levels of serum baseline tryptase (P= .01), IFN-γ (P= .05), IL-1β (P= .05), and IL-6 (P= .05) versus those found in patients with healthy bone. In contrast, patients with diffuse bone sclerosis showed significantly higher levels of serum baseline tryptase (P < .001), C-terminal telopeptide (P < .001), amino-terminal propeptide of type I procollagen (P < .001), osteocalcin (P < .001), bone alkaline phosphatase (P < .001), osteopontin (P< .01), and the C-C Motif Chemokine Ligand 5/RANTES chemokine (P= .01), together with lower IFN-γ (P= .03) and RANK-ligand (P= .04) plasma levels versus healthy bone cases. SM with bone mass loss is associated with a proinflammatory cytokine profile in plasma, whereas diffuse bone sclerosis shows increased serum/plasma levels of biomarkers related to bone formation and turnover, in association with an immunosuppressive cytokine secretion profile.

The nanoformula of zoledronic acid and calcium carbonate targets osteoclasts and reverses osteoporosis

Osteoporosis is known as an imbalance in bone catabolism and anabolism. Overactive bone resorption causes bone mass loss and increased incidence of fragility fractures. Antiresorptive drugs are widely used for osteoporosis treatment, and their inhibitory effects on osteoclasts (OCs) have been well established. However, due to the lack of selectivity, their off-target and side effects often bring suffering to patients. Herein, an OCs’ microenvironment-responsive nanoplatform HA-MC/CaCO3/ZOL@PBAE-SA (HMCZP) is developed, consisting of succinic anhydride (SA)-modified poly(β-amino ester) (PBAE) micelle, calcium carbonate shell, minocycline-modified hyaluronic acid (HA-MC) and zoledronic acid (ZOL). Results indicate that HMCZP, as compared with the first-line therapy, could more effectively inhibit the activity of mature OCs and significantly reverse the systemic bone mass loss in ovariectomized mice. In addition, the OCs-targeted capacity of HMCZP makes it therapeutically efficient at sites of severe bone mass loss and allows it to reduce the adverse effects of ZOL, such as acute phase reaction. High-throughput RNA sequencing (RNA-seq) reveals that HMCZP could down-regulate a critical osteoporotic target, tartrate-resistant acid phosphatase (TRAP), as well as other potential therapeutical targets for osteoporosis. These results suggest that an intelligent nanoplatform targeting OCs is a promising strategy for osteoporosis therapy.

Lyophilized powder of velvet antler blood improves osteoporosis in OVX-induced mouse model and regulates proliferation and differentiation of primary osteoblasts via Wnt/β-catenin pathway

The lyophilized powder of velvet antler blood (VAB) is a by-product of pilose antler, a supplement rich in amino acids, fatty acids, trace elements and vitamins, and it is expected to have anti-osteoporosis effects. The aim of our study was to provide a comprehensive assessment of the anti-osteoporosis effects of VAB in vivo and in vitro. In vivo results indicated that VAB had the protective effects on bone tissue microarchitecture degeneration and bone mass loss in ovariectomized mice. Through an in vitro study, the ability of VAB to promote proliferation, migration and differentiation of primary osteoblasts was confirmed. Further studies have shown that VAB influences cell cycle by regulating Wnt/β-catenin signaling pathway, thus promoting proliferation and differentiation of primary osteoblasts and preventing osteoporosis. According to our research results, VAB is considered to be a potential anti-osteoporosis nutrient, which may help to improve the quality of life of patients with osteoporosis.

Treadmill Exercise Suppresses Histological Progression of Disuse Atrophy in Articular Cartilage in Rat Knee Joints during Hindlimb Suspension.

The purpose of this study was to determine the preventive effects of treadmill exercise or physiological loading on disuse atrophy in the rat knee joint cartilage and bone during hindlimb suspension. Twenty male rats were divided into 4 experimental groups, including the control, hindlimb suspension, physiological loading, and treadmill walking groups. Histological changes in the articular cartilage and bone of the tibia were histomorphometrically and immunohistochemically evaluated 4 weeks after the intervention. Compared with the control group, the hindlimb suspension group showed thinning of cartilage thickness, decreased matrix staining, and decreased proportion of noncalcified layers. Cartilage thinning, decreased matrix staining, and decreased noncalcified layers were suppressed in the treadmill walking group. The physiological loading group exhibited no significant suppression of cartilage thinning or decreased noncalcified layers, but the decreased matrix staining was significantly suppressed. No significant prevention of bone mass loss or changes in subchondral bone thickness were detected after physiological loading or treadmill walking. Disuse atrophy of the articular cartilage caused by unloading conditions could be prevented by treadmill walking in rat knee joints.

Long-term functional results of revision hip replacement using Burch-Schneider cages

IntroductionOne of the most common and effective treatments for end-stage hip osteoarthritis is total hip arthroplasty (THA). According to the WHO, 1.5 million, more than 500,000, and approximately 100,000 THAs are performed annually in the world, in the USA, and in Russia, respectively. The use of Burch-Schneider cages has progressively increased since their introduction in 1975, with more than 125,000 cages being implanted by 2006. This design for revision surgery remains valid today.The objectives were to conduct a retrospective analysis of anti-protrusion cages in revision THA and evaluate long-term functional results. MethodsFifty-eight revision surgeries were performed at Botkin Hospital from 2003 to 2020 with anti-protrusion Burch-Schneider cages because of aseptic loosening of the acetabular component. The average age of the examined patients was 61.2 (±12.9) years. The maximum follow-up duration was 17 years. The average follow-up duration was 10.5 (±4.1) years. We used the functional Harris, WOMAC, SF-36, and FJS-12 scales to evaluate functional results. The patients were distributed into the following groups according to the Paprosky classification: 2C, 3A, and 3B. ResultsGroup 2C showed good functional results, with a Harris score of 87 (±6.9), an FJS-12 score of 63.2 (±4.8), a WOMAC score of 175 (±16.7), and an Oxford Hip score of 39.06 (±9.1). Group 3A also showed good functional scores, with a Harris score of 78 (±7.1), an FJS-12 score of 61.2 (±5.1), a WOMAC score of 168 (±17.1), and an Oxford Hip score of 42.12 (±8.7). Group 3B showed satisfactory functional results, with a Harris score of 70 (±5.9), an FJS-12 score of 58.9 (±4.4), a WOMAC score of 166 (±18.1), and an Oxford Hip score of 48.4 (±9.4).Among patients who underwent revision surgery using Burch-Schneider rings, 16 needed to undergo repeat revision surgery. Periprosthetic infection occurred in 5 patients, aseptic loosening in 7, and periprosthetic fracture in 3. ConclusionsThe anti-protrusion Burch-Schneider system is a necessary and up-to-date element of THA and can be used with great efficacy in revision THA. Despite the rapid development of technologies and the appearance of new, highly efficient devices, there is still room for systems such as Burch-Schneider rings. However, there are relatively few indications for their use, with the main indications for the use of anti-protrusion systems being conditions related to bone defects of the acetabular roof and bone mass loss of the acetabular floor.

Pathophysiological Aspects of Muscle Atrophy and Osteopenia Induced by Chronic Constriction Injury (CCI) of the Sciatic Nerve in Rats.

Skeletal muscle atrophy is a condition characterized by a loss of muscle mass and muscle strength caused by an imbalance between protein synthesis and protein degradation. Muscle atrophy is often associated with a loss of bone mass manifesting as osteoporosis. The aim of this study was to evaluate if chronic constriction injury (CCI) of the sciatic nerve in rats can be a valid model to study muscle atrophy and consequent osteoporosis. Body weight and body composition were assessed weekly. Magnetic resonance imaging (MRI) was performed on day zero before ligation and day 28 before sacrifice. Catabolic markers were assessed via Western blot and Quantitative Real-time PCR. After the sacrifice, a morphological analysis of the gastrocnemius muscle and Micro-Computed Tomography (Micro-CT) on the tibia bone were performed. Rats that underwent CCI had a lower body weight increase on day 28 compared to the naive group of rats (p < 0.001). Increases in lean body mass and fat mass were also significantly lower in the CCI group (p < 0.001). The weight of skeletal muscles was found to be significantly lower in the ipsilateral hindlimb compared to that of contralateral muscles; furthermore, the cross-sectional area of muscle fibers decreased significantly in the ipsilateral gastrocnemius. The CCI of the sciatic nerve induced a statistically significant increase in autophagic and UPS (Ubiquitin Proteasome System) markers and a statistically significant increase in Pax-7 (Paired Box-7) expression. Micro-CT showed a statistically significant decrease in the bone parameters of the ipsilateral tibial bone. Chronic nerve constriction appeared to be a valid model for inducing the condition of muscle atrophy, also causing changes in bone microstructure and leading to osteoporosis. Therefore, sciatic nerve constriction could be a valid approach to study muscle-bone crosstalk and to identify new strategies to prevent osteosarcopenia.