Epigenetic regulations of cellular senescence in osteoporosis.

Osteoporosis (OP) is a prevalent age-related disease that is characterized by a decrease in bone mineral density (BMD) and systemic bone microarchitectural disorders. With age, senescent cells accumulate and exhibit the senescence-associated secretory phenotype (SASP) in bone tissue, leading to the imbalance of bone homeostasis, osteopenia, changes in trabecular bone structure, and increased bone fragility. Cellular senescence in the bone microenvironment involves osteoblasts, osteoclasts, and bone marrow mesenchymal stem cells (BMSCs), whose effects on bone homeostasis are regulated by epigenetics. Therefore, the epigenetic regulatory mechanisms of cellular senescence have received considerable attention as potential targets for preventing and treating osteoporosis. In this paper, we systematically review the mechanisms of aging-associated epigenetic regulation in osteoporosis, emphasizing the impact of epigenetics on cellular senescence, and summarize three current methods of targeting cellular senescence, which is helpful better to understand the pathogenic mechanisms of cellular senescence in osteoporosis and provides strategies for the development of epigenetic drugs for the treatment of osteoporosis.

The bone-liver interaction modulates immune and hematopoietic function through Pinch-Cxcl12-Mbl2 pathway.

Mesenchymal stromal cells (MSCs) are used to treat infectious and immune diseases and disorders; however, its mechanism(s) remain incompletely defined. Here we find that bone marrow stromal cells (BMSCs) lacking Pinch1/2 proteins display dramatically reduced ability to suppress lipopolysaccharide (LPS)-induced acute lung injury and dextran sulfate sodium (DSS)-induced inflammatory bowel disease in mice. Prx1-Cre; Pinch1f/f; Pinch2-/- transgenic mice have severe defects in both immune and hematopoietic functions, resulting in premature death, which can be restored by intravenous injection of wild-type BMSCs. Single cell sequencing analyses reveal dramatic alterations in subpopulations of the BMSCs in Pinch mutant mice. Pinch loss in Prx1+ cells blocks differentiation and maturation of hematopoietic cells in the bone marrow and increases production of pro-inflammatory cytokines TNF-α and IL-1ß in monocytes. We find that Pinch is critical for expression of Cxcl12 in BMSCs; reduced production of Cxcl12 protein from Pinch-deficient BMSCs reduces expression of the Mbl2 complement in hepatocytes, thus impairing the innate immunity and thereby contributing to infection and death. Administration of recombinant Mbl2 protein restores the lethality induced by Pinch loss in mice. Collectively, we demonstrate that the novel Pinch-Cxcl12-Mbl2 signaling pathway promotes the interactions between bone and liver to modulate immunity and hematopoiesis and may provide a useful therapeutic target for immune and infectious diseases.

Pathological progress and remission strategies of osteoarthritic lesions caused by long-term joint immobilization.

OBJECTIVE: While joint immobilization is a useful repair method for intra-articular ligament injury and periarticular fracture, prolonged joint immobilization can cause multiple complications. A better understanding how joint immobilization and remobilization impact joint function and homeostasis will help clinicians develop novel strategies to reduce complications. DESIGN: We first determined the effects of long-term immobilization on joint pain and osteophyte formation in patients after an extraarticular fracture or ligament injury. We then developed a mouse model of joint immobilization and harvested the knee joint samples at 2, 4, and 8 weeks. We further determined the effects of remobilization on recovery of the osteoarthritis (OA) lesions induced by immobilization in mice. RESULTS: We found that the long-term (6 weeks) joint immobilization caused significant joint pain and osteophytes in patients. In mice, 2-week immobilization already induced moderate sensory innervation and increased pain sensitivity and infiltration in synovium without inducing marked osteophyte formation and cartilage loss. Long-term immobilization (4 and 8 weeks) induced more severe sensory innervation and inflammatory infiltration in synovium, massive osteophyte formation on both sides of the femoral condyle, and the edge of the tibial plateau and significant loss of the articular cartilage in mice. Remobilization, which ameliorates normal joint load and activity, restored to certain extent some of the OA lesions and joint function in mice. CONCLUSIONS: Joint immobilization caused multiple OA-like lesions in both mice and humans. Joint immobilization induced progressive sensory innervation, synovitis, osteophyte formation, and cartilage loss in mice, which can be partially ameliorated by remobilization.

Integrating network pharmacology and experimental verification strategies to reveal the active ingredients and molecular mechanism of Tenghuang Jiangu Capsule against osteoporosis.

Tenghuang Jiangu Capsule (THJGC) is a Chinese herbal formula used for the treatment of osteoporosis and osteoarthritis in China, but its mechanism for treating osteoporosis is not clear. The aim of this study was to investigate the therapeutic effect of THJGC on osteoporosis and its intrinsic mechanism through network pharmacology and experimental validation. Drugs and potential targets were obtained from several reliable databases through network pharmacology, and these targets were integrated and analyzed using bioinformatics and molecular docking strategies. Quercetin, lignans and kaempferol were identified as key components, and the key targets included Akt1, MAPKs, and CASP3. Subsequently, UPLC-MS/MS analysis confirmed the presence of components in THJGC for the treatment of osteoporosis. In addition, using ex vivo and in vivo models, it was confirmed that THJGC inhibited H2O2-induced ROS generation and apoptosis, and reduced OVX-induced bone loss in a mouse model of osteoporosis. Our data suggest that THJGC has antioxidant, bone formation-promoting, bone resorption-inhibiting, and MC3T3-E1 apoptosis-reducing effects, and thus has anti-osteoporotic properties. In conclusion, it may be a promising pharmacologic adjuvant treatment for osteoporosis.

Piezo1 activation accelerates osteoarthritis progression and the targeted therapy effect of artemisinin.

INTRODUCTION: Osteoarthritis (OA) is a devastating whole-joint disease affecting a large population worldwide with no cure; its mechanism remains poorly defined. Abnormal mechanical stress is the main pathological factor of OA. OBJECTIVES: To investigate the effects of Piezo1 activation on OA development and progression and to explore Piezo1-targeting OA treatment. METHODS: The expression levels of Piezo1 were determined in human OA cartilage and experimental OA mice. Mice with genetic Piezo1 deletion in chondrocytes or intra-articular injection of the Piezo1 activator Yoda1 were utilized to determine the effects on DMM-induced OA progression. Effects of artemisinin (ART), a potent antimalarial drug, on Piezo1 activation, chondrocyte metabolism and OA lesions were determined. RESULTS: Piezo1 expression was elevated in articular chondrocytes in human OA and DMM-induced mouse OA cartilage. Piezo1 deletion in chondrocytes largely attenuates DMM-induced OA-like phenotypes. In contrast, intra-articular injection of Yoda1 aggravates the knee joint OA lesions in mice. PIEZO1 activation increases, while PIEZO1 siRNA knockdown decreases, expression of RUNX2 and catabolic enzymes MMP13 and ADAMTS5 in primary human articular chondrocytes in a PI3K-AKT dependent manner. We have provided strong evidence supporting that ART is a novel and potent inhibitor of Piezo1 activation in primary OA-HACs and all cell lines examined, including human endothelial HUVEC cells, ATDC5 chondrocyte-like cells and MLO-Y4 osteocytes-like cells. Results from in vitro experiments confirmed that ART decreases the Yoda1-induced increases in the levels of OA-related genes and p-PI3K and p-AKT proteins in OA-HACs and alleviates DMM-induced OA lesions in mice. CONCLUSIONS: We establish a critical role of Piezo1 in promoting OA development and progression and define ART as a potential OA treatment.

Pip5k1c Loss in Chondrocytes Causes Spontaneous Osteoarthritic Lesions in Aged Mice.

Osteoarthritis (OA) is the most common degenerative joint disease affecting the older populations globally. Phosphatidylinositol-4-phosphate 5-kinase type-1 gamma (Pip5k1c), a lipid kinase catalyzing the synthesis of phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), is involved in various cellular processes, such as focal adhesion (FA) formation, cell migration, and cellular signal transduction. However, whether Pip5k1c plays a role in the pathogenesis of OA remains unclear. Here we show that inducible deletion of Pip5k1c in aggrecan-expressing chondrocytes (cKO) causes multiple spontaneous OA-like lesions, including cartilage degradation, surface fissures, subchondral sclerosis, meniscus deformation, synovial hyperplasia, and osteophyte formation in aged (15-month-old) mice, but not in adult (7-month-old) mice. Pip5k1c loss promotes extracellular matrix (ECM) degradation, chondrocyte hypertrophy and apoptosis, and inhibits chondrocyte proliferation in the articular cartilage of aged mice. Pip5k1c loss dramatically downregulates the expressions of several key FA proteins, including activated integrin ß1, talin, and vinculin, and thus impairs the chondrocyte adhesion and spreading on ECM. Collectively, these findings suggest that Pip5k1c expression in chondrocytes plays a critical role in maintaining articular cartilage homeostasis and protecting against age-related OA.

MicroRNAs and long non-coding RNAs in cartilage homeostasis and osteoarthritis.

During the last decade, osteoarthritis (OA) has become one of the most prevalent musculoskeletal diseases worldwide. OA is characterized by progressive loss of articular cartilage, abnormal remodeling of subchondral bone, hyperplasia of synovial cells, and growth of osteophytes, which lead to chronic pain and disability. The pathological mechanisms underlying OA initiation and progression are still poorly understood. Non-coding RNAs (ncRNAs) constitute a large portion of the transcriptome that do not encode proteins but function in numerous biological processes. Cumulating evidence has revealed a strong association between the changes in expression levels of ncRNA and the disease progression of OA. Moreover, loss- and gain-of-function studies utilizing transgenic animal models have demonstrated that ncRNAs exert vital functions in regulating cartilage homeostasis, degeneration, and regeneration, and changes in ncRNA expression can promote or decelerate the progression of OA through distinct molecular mechanisms. Recent studies highlighted the potential of ncRNAs to serve as diagnostic biomarkers, prognostic indicators, and therapeutic targets for OA. MiRNAs and lncRNAs are two major classes of ncRNAs that have been the most widely studied in cartilage tissues. In this review, we focused on miRNAs and lncRNAs and provided a comprehensive understanding of their functional roles as well as molecular mechanisms in cartilage homeostasis and OA pathogenesis.

Identification of Interleukin-1-Beta Inhibitors in Gouty Arthritis Using an Integrated Approach Based on Network Pharmacology, Molecular Docking, and Cell Experiments.

Background: This study aimed to investigate the molecular mechanism of Tongfengding capsule (TFDC) in treating immune-inflammatory diseases of gouty arthritis (GA) and interleukin-1-beta (IL-1ß) inhibitors by using network pharmacology, molecular docking, and cell experiments. Methods: In this study, the compounds of TFDC and the potential inflammatory targets of GA were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Online Mendelian Inheritance in Man (OMIM), and GeneCards databases. The TFDC-GA-potential targets interaction network was accomplished by the STRING database. The TFDC-active compound-potential target-GA network was constructed using Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to further explore the GA mechanism and therapeutic effects of TFDC. Quantitative real-time PCR (qPCR) was used to verify whether the TFDC inhibited IL-1ß in GA. Molecular docking technology was used to analyze the optimal effective compounds from the TFDC for docking with IL-1ß. Result: 133 active compounds and 242 targets were screened from the TFDC, and 25 of the targets intersected with GA inflammatory targets, which were considered as potential therapeutic targets. Network pharmacological analysis showed that the TFDC active compounds such as quercetin, stigmasterol, betavulgarin, rutaecarpine, naringenin, dihydrochelerythrine, and dihydrosanguinarine had better correlation with GA inflammatory targets such as PTGS2, PTGS1, NOS2, SLC6A3, HTR3A, PPARG, MAPK14, RELA, MMP9, and MMP2. The immune-inflammatory signaling pathways of the active compounds for treating GA are IL-17 signaling pathway, TNF signaling pathway, NOD-like receptor signaling pathway, NF-kappa B signaling pathway, Toll-like receptor signaling pathway, HIF-1 signaling pathway, etc. The TFDC reduced IL-1ß mRNA expression in GA by qPCR. Molecular docking results suggested that rutaecarpine was the most appropriate natural IL-1ß inhibitor. Conclusion: Our findings provide an essential role and bases for further immune-inflammatory studies on the molecular mechanisms of TFDC and IL-1ß inhibitors development in GA.

Histone H3K9 demethylase JMJD2B/KDM4B promotes osteogenic differentiation of bone marrow-derived mesenchymal stem cells by regulating H3K9me2 on RUNX2.

Background: A variety of proteins including epigenetic factors are involved in the differentiation of human bone marrow mesenchymal stem cells. These cells also exhibited an epigenetic plasticity that enabled them to trans-differentiate from adipocytes to osteoblasts (and vice versa) after commitment. Further in-depth study of their epigenetic alterations may make sense. Methods: Chromatin Immunoprecipitation-PCR (ChIP-PCR) was used to detect the methylation enrichment status of H3K9me2 in the Runx2 promoter, alizarin red and alkaline phosphatase (ALP) staining were used to detect osteogenic differentiation and mineralization ability, western blot and quantitative RT-PCR were used to measure the differential expression of osteogenesis-related proteins and genes. Recombinant Lentivirus mediated gain-of-function and loss-of-function study. The scale of epigenetic modification was detected by laser confocal. Results: Our results showed that compared with human bone marrow mesenchymal stem cells (hBMSCs) without osteogenic differentiation treatment, hBMSCs after osteogenic differentiation significantly promoted osteogenic differentiation and mRNA expression such as JMJD2B/KDM4B, osteogenesis-related genes like Runx2 and FAM210A in hBMSCs cells, suggesting that upregulation of JMJD2B/KDM4B is involved in the promoting effect of osteogenesis. After overexpression and silencing expression of JMJD2B, we found a completely opposite and significant difference in mRNA expression of osteogenesis-related genes and staining in hBMSCs. Overexpression of JMJD2B/KDM4B significantly promoted osteogenic differentiation, suggesting that JMJD2B/KDM4B could promote osteogenesis. In addition, ChIP-PCR showed that overexpression of JMJD2B/KDM4B significantly reversed the methylation enrichment status of H3K9me2 in Runx2 promoter. Furthermore, overexpression of JMJD2B/KDM4B significantly reverses the inhibitory effect of BIX01294 on H3K9me2, suggesting that JMJD2B/KDM4B regulates the osteogenic differentiation of hBMSCs by changing the methylation status of H3K9me2 at the Runx2 promoter. Conclusions: Taken together, these results suggest that JMJD2B/ KDM4B may induce the osteogenic differentiation of hBMSCs by regulating the methylation level of H3K9me2 at the Runx2 promoter.

A Network Pharmacology and Molecular Docking Strategy to Explore Potential Targets and Mechanisms Underlying the Effect of Curcumin on Osteonecrosis of the Femoral Head in Systemic Lupus Erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a refractory immune disease, which is often complicated with osteonecrosis of the femoral head (ONFH). Curcumin, the most active ingredient of Curcuma longa with a variety of biological activities, has wide effects on the body system. The study is aimed at exploring the potential therapeutic targets underlying the effect of curcumin on SLE-ONFH by utilizing a network pharmacology approach and molecular docking strategy. METHODS: Curcumin and its drug targets were identified using network analysis. First, the Swiss target prediction, GeneCards, and OMIM databases were mined for information relevant to the prediction of curcumin targets and SLE-ONFH-related targets. Second, the curcumin target gene, SLE-ONFH shared gene, and curcumin-SLE-ONFH target gene networks were created in Cytoscape software followed by collecting the candidate targets of each component by R software. Third, the targets and enriched pathways were examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Eventually, a gene-pathway network was constructed and visualized by Cytoscape software; key potential central targets were verified and checked by molecular docking and literature review. RESULTS: 201 potential targets of curcumin and 170 related targets involved in SLE-ONFH were subjected to network analysis, and the 36 intersection targets indicated the potential targets of curcumin for the treatment of SLE-ONFH. Additionally, for getting more comprehensive and accurate candidate genes, the 36 potential targets were determined to be analyzed by network topology and 285 candidate genes were obtained finally. The top 20 biological processes, cellular components, and molecular functions were identified, when corrected by a P value ≤ 0.05. 20 related signaling pathways were identified by KEGG analysis, when corrected according to a Bonferroni P value ≤ 0.05. Molecular docking showed that the top three genes (TP53, IL6, VEGFA) have good binding force with curcumin; combined with literature review, some other genes such as TNF, CCND1, CASP3, and MMP9 were also identified. CONCLUSION: The present study explored the potential targets and signaling pathways of curcumin against SLE-ONFH, which could provide a better understanding of its effects in terms of regulating cell cycle, angiogenesis, immunosuppression, inflammation, and bone destruction.

Silencing of MEF2D by siRNA Loaded Selenium Nanoparticles for Ovarian Cancer Therapy.

BACKGROUND: Delivery of therapeutic small interfering RNA (siRNA) via functionalized nanoparticles holds great promise for cancer therapy. However, developing a safe and efficient delivery carrier of siRNA is a challenging issue. METHODS: RGDfC peptide was used to modify the surface of selenium nanoparticles (SeNPs) to synthesize a biocompatible siRNA delivery vehicle (R-SeNPs), and MEF2D-siRNA was loaded onto R-SeNPs to prepare a functionalized selenium nanoparticle R-Se@MEF2D-siRNA. The chemical properties of R-SeNPs were characterized, and the anticancer efficacy as well as related mechanisms of R-Se@MEF2D-siRNA were further explored. RESULTS: R-Se@MEF2D-siRNA was significantly taken up by SKOV3 cells and could enter SKOV3 cells mainly in the clathrin-associated endocytosis way. The result of in vitro siRNA release demonstrated that R-Se@MEF2D-siRNA could release MEF2D-siRNA quicker in a microenvironment simulating a lysosomal environment in tumor cells compared to a normal physiological environment. The results of qRT-PCR assay proved that R-Se@MEF2D-siRNA could effectively silence the expression of the MEF2D gene in SKOV3 cells. R-Se@MEF2D-siRNA remarkably suppressed the proliferation of SKOV3 cells and further triggered its apoptosis. In addition, R-Se@MEF2D-siRNA had the capability to disrupt mitochondrial membrane potential (MMP) in SKOV3 cells and resulted in the overproduction of reactive oxygen species (ROS), indicating that mitochondrial dysfunction and ROS generation played an important role in the apoptosis of SKOV3 cells induced by R-Se@MEF2D-siRNA. In vivo, R-Se@MEF2D-siRNA also exhibited excellent antitumor activity mainly through decreasing tumor cells proliferation and triggering their apoptosis in tumor-bearing nude mice. CONCLUSION: R-Se@MEF2D-siRNA provides an alternative strategy for ovarian cancer treatment in the clinic.

Lysine-Specific Demethylase 4A Regulates Osteogenic Differentiation via Regulating the Binding Ability of H3K9me3 with the Promoters of Runx2, Osterix and Osteocalcin.

A well-studied subject of epigenetics, the histone methylation located at lysine and arginine is overseen via methyltransferases and demethylases. Lysine-specific demethylase 4A (KDM4A) comprises a lysine demethylase and possesses specificity for H3K9me3 and H3K36me3, which is capable of being used in order to activate histone transcription. Our team examined the expression of KDM4A within Sprague Dawley (SD) rats and further investigated the mechanism via which this phenomena regulates osteogenic variation within the present study. The overexpression of KDM4A facilitated the process of osteoblast differentiation in bone mesenchymal stem cells (BMSC), while the knocking down differentiation via osteoblast was restrained via the suppression of the expression of Runx2, Osterix, alkaline phosphatase (ALP), and osteocalcin (OCN). Knocking down KDM4A lowered levels of the promoter expression of Runx2, osterix, and OCN, and raised levels of H3K27me3 expression. The results demonstrated that KDM4A possesses a crucial role within the differentiation of osteoblasts and furthermore regulates the expression of Runx2, Osterix, and OCN via H3K9me3. The present research may provide new insights into the treatment of bone healing.

lncRNA GAS8-AS1 downregulates lncRNA UCA1 to inhibit osteosarcoma cell migration and invasion.

BACKGROUND: Osteosarcoma (OS) is the most common type of primary bone tumor that mainly affects adolescents and young adults. The present study explored the role of lncRNA GAS8-AS1 in OS. METHODS: A total of 48 OS patients were selected from the 82 OS patients admitted by Luoyang Orthopedic Hospital of Henan Province between May 2010 and May 2013. Transient cell transfections, Transwell cell migration and invasion assay, RT-qPCR, and patient follow-up were carried out during the research. RESULTS: The results showed that GAS8-AS1 was downregulated, while UCA1 was upregulate in cancer tissues in comparison to adjacent non-cancer tissues of OS patients. GAS8-AS1 was not affected by clinical stage. Follow-up study showed that downregulated GAS8-AS1 in cancer tissues was closely correlated with poor survival. GAS8-AS1 and UCA1 were inversely correlated in cancer tissues. Overexpression of UCA1 failed to affect the expression of GAS8-AS1, while overexpression of GAS8-AS1 led to downregulated expression of UCA1 in OS cells, while the molecular mediators between these two lncRNAs are unknown. Overexpression of GAS8-AS1 did not affect OS cell proliferation but significantly inhibited cancer cell migration and invasion. Overexpression of UCA1 promoted the migration and invasion of OS cells and attenuated the effects of overexpressing GAS8-AS1. CONCLUSIONS: Therefore, GAS8-AS1 may inhibit OS cell migration and invasion by downregulating oncogenic UCA1.

The protective effects of bexarotene against advanced glycation end-product (AGE)-induced degradation of articular extracellular matrix (ECM).

Osteoarthritis (OA) is a common debilitating disease primarily characterised by excessive loss of the articular ECM, which is composed of up to 95% type II collagen. Among the factors that contribute to the pathogenesis of OA, the natural process of aging is regarded as the most significant risk factor. AGEs, which are extremely resilient to degradation, are produced in the body naturally as a result of the Maillard process of nonenzymatic glycation and are also introduced through diet and tobacco smoke. AGEs have a high affinity for collagen and therefore accumulate in joint tissues, where they induce increased expression of proinflammatory cytokines, chemokines, and degradative enzymes. Additionally, AGEs induce oxidative stress, which further exacerbates the degradative process. Type II collagen is targeted for degradation by matrix metalloproteinases (MMPs), particularly MMP-3 and MMP-13, and AGEs have been shown to trigger increased expression of these MMPs. The role of retinoid and rexinoid receptors as specific treatment targets has been receiving increasing attention. Bexarotene is a retinoid X receptor (RXR) agonist used for the treatment of T-cell lymphoma and other cancers which has displayed a favourable safety profile. Here, we examined the roles of RXR agonism using bexarotene on AGE-induced markers of OA, including oxidative stress, inflammatory response, and MMP-mediated degradation of type II collagen. Furthermore, we demonstrate that bexarotene inhibited phosphorylation of IκBα, thereby suppressing activation of the proinflammatory NF-κB cellular signalling pathway. These findings present a basis for selective targeting of RXR by bexarotene as a potential treatment of OA induced by AGEs.

The efficacy of Chinese patent medicine combined with entecavir for the treatment of chronic HBV-related liver fibrosis or cirrhosis: Protocol for a systematic review and meta-analysis of randomized controlled trials or prospective cohort studies.

BACKGROUND: There are currently no FDA-approved biological or chemical drugs for the treatment of HBV-related liver fibrosis or cirrhosis. Some Chinese patent medicines have proven to be effective in this area. OBJECTIVE: The network meta-analysis (NMA) is to evaluate whether entecavir combined with Chinese patent medicine, such as "fuzhenghuayu capsules," "anluohuaxian pills," "fufangbiejiaruangan tablets," shows superior efficiency compared with entecavir alone for the treatment of chronic HBV-related liver fibrosis or cirrhosis. To evaluate which Chinese patent medicine is the most effective at improving liver fibrosis or cirrhosis in chronic hepatitis B-infected patients? METHODS: Registration of protocol: the protocol was published in the PROSPERO database (identification number: CRD42018112547). We will search PubMed, EMbase, Medline, Cochrane, China Network Knowledge Infrastructure (CNKI), and Wanfang for randomized controlled trials (RCTs) or "prospective cohort studies" of "fuzhenghuayu capsules," "anluohuaxian pills," "fufangbiejiaruangan tablets" respectively combined with entecavir in the treatment of chronic HBV-related liver fibrosis or cirrhosis from their inception to September 30, 2018. R 3.3.3 and GeMTC 0.14.3 software will be used for data analysis.

Activation of GPER suppresses the malignancy of osteosarcoma cells via down regulation of IL-6 and IL-8.

Estrogenic signals can regulate the progression of osteosarcoma (OS) via classic estrogen receptor α/ß (ERα/ß). G protein-coupled estrogen receptor (GPER) can mediate the non-genomic effects of estrogen and regulate the progression of various cancers. Our present study revealed that the expression of GPER in OS cells and tissues was lower than that in their corresponding controls. Activation of GPER via its specific agonist G-1 can decrease the proliferation, migration, and invasion of OS cells. By screening the expression of cytokines involved in the progression of OS, we found that activation of GPER can inhibit the expression of interleukin-6 (IL-6) and IL-8 in OS cells. Recombinant IL-6 (rIL-6) or rIL-8 can attenuate G-1 suppressed migration of OS cells. Mechanically, activation of GPER can rapidly decease the phosphorylation and nuclear translocation of NF-κB in OS cells. While over expression of p65 significantly attenuated G-1 induced down regulation of IL-6/IL-8. Further, G-1 can decrease the activation of p38-MAPK, which can further shorten the half-life of IL-8 mRNA. Collectively, we revealed that GPER can suppress the migration and invasion of OS cells via inhibition of IL-6 and IL-8. It suggested that GPER might be a potential therapy target for OS treatment.

Short-stem prostheses in primary total hip arthroplasty: A meta-analysis of randomized controlled trials.

BACKGROUND: Short-stem (SS) prostheses require less resection of the femoral neck, produce a more physiological load pattern in the proximal femur, reduce stress shielding, and aid bone conservation and are, therefore, beneficial for young patients. Conventional cementless implants in total hip arthroplasty (THA) have shown excellent clinical results; however, it is unclear whether SS prostheses can obtain the same clinical and radiological outcomes. We conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate whether SS prostheses are superior to conventional implants after primary THA. METHODS: We reviewed the literature published up to June 2016 from PubMed, Web of Science, and the Cochrane Library to find relevant RCTs comparing SSs and conventional stems in primary THA. Quality assessment was performed by 2 independent reviewers. The RevMan 5.3 software program of the Cochrane Collaboration was used to analyze the data. Random- or fixed-effect models were used to calculate standardized mean differences (SMDs) and 95% confidence intervals (CIs) for each comparison. RESULTS: Six RCTs involving 552 patients with 572 hips were identified. Strong evidence indicated that SS prostheses were more effective for reducing thigh pain than conventional implants (I = 46%, P = 0.002; risk ratio [RR], 95% CI 0.15, 0.04-0.49). However, there were no significant differences between the 2 groups in Harris Hip Scores (I = 0%, P = 0.84; SMD, 95% CI 0.02, -0.15-0.18), Western Ontario and McMaster Universities Osteoarthritis Index Scores (I = 0%, P = 0.35; SMD, 95% CI 0.09, -0.10-0.27), femoral offset of stem (I = 0%, P = 0.57; SMD, 95% CI 0.06, -0.16-0.29), and leg-length discrepancy (I = 79%, P = 0.88; SMD, 95% CI 0.04, -0.44-0.51). CONCLUSION: SS prostheses achieve the same clinical and radiological outcomes as conventional implants, and were superior in terms of reducing thigh pain. But whether the postoperative thigh pain applied in 2nd-generation cementless prosthesis still needs further large-scale multicenter studies with longer follow-up to confirm.

The failure experience of complex total hip arthroplastyin osteopetrosis: case report and literature review.

There is rare literature elaborating the complex total hip arthroplasty (THA) in patients with osteopetrosis who experienced malunion from femoral neck fracture. We have summarized the failure experience of the complex THA in osteopetrosis. Learned from the resurgery in the case reported by this paper, we recommend to highlight the initial stability of the prosthesis and not to overestimate the potency of fracture healing in the complex THA in osteopetrosis.

[EFFECTIVENESS OF UC ULTRA-CONGRUENT ROTATING PLATFORM PROSTHESIS IN TREATMENT OF KNEE OSTEOARTHRITIS].

OBJECTIVE: To explore the effectiveness of UC ultra-congruent rotating platform prosthesis in the treatment of knee osteoarthritis by comparing with fixed-bearing implant. METHODS: The clinical data were retrospectively analyzed, from 98 patients (98 knees) with knee osteoarthritis undergoing primary total knee arthroplasty between January 2011 and December 2012. The UC ultra-congruent rotating platform prosthesis was used in 56 cases (mobile-bearing group) and fixed-bearing implant was used in 42 cases (fixed-bearing group). There was no significant difference in gender, age, side, weight, disease duration, grading of arthritis, the number of varus and valgus malformation, preoperative range of motion of the knee, the Knee Society Score (KSS) score, the visual analogue scale (VAS) score, femorotibial angle, tibial angle, and articular surface angle between 2 groups (P > 0.05). The operation time (including anesthetic time), intraoperative blood loss, hospitalization time, total hospitalization expenses, postoperative range of motion of the knee, the KSS score, and the VAS score were compared. The femorotibial angle, tibial angle, and articular surface angle were measured on the basis of anteroposterior and lateral X-ray films, and prosthesis loosening was observed. RESULTS: There was no significant difference in the operation time, intraoperative blood loss, and hospitalization time between 2 groups (P > 0.05), while the total hospitalization expenses of fixed-bearing group were significantly lower than those of the mobile-bearing group (t = 8.506, P = 0.000). The patients were followed up 16-30 months in the mobile-bearing group, and for 16-38 months in the fixed-bearing group. Postoperative complications occurred in 3 cases (7.14%) of the fixed-bearing group (1 case of fat liquefaction of incision, 1 case of joint stiff, and 1 case of anterior knee pain), and in 3 cases (5.36%) of the mobile-bearing group (1 case of delayed wound healing, and 2 cases of anterior knee pain); there was no significant difference in the complication rate between 2 groups (χ2 = 0.133, P = 0.516). At last follow-up, the KSS score, VAS score, range of motion of the knee, femorotibial angle, tibial angle, and articular surface angle were superior significantly to those before operation in both groups (P < 0.05), but no significant difference was found between 2 groups (P > 0.05). No radiographic signs of radiolucent line, prosthetic dislocation, patellar dislocation, prosthetic loosening, and fracture was found. CONCLUSION: UC ultra-congruent rotating platform prosthesis in the treatment of knee osteoarthritis can effectively improve the knee joint function and relief pain, which has the same short-term effectiveness in fixed bearing implant.

Effect of whole body vibration therapy on circulating serotonin levels in an ovariectomized rat model of osteoporosis.

OBJECTIVE(S): Studies have reported that whole body vibration (WBV) played a vital role in bone remodeling. Circulating serotonin is also involved in negative regulating bone mass in rodents and humans. However, both WBV and inhibition of serotonin biosynthesis may suppress receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis in vitro. The purpose of the current study was to investigate the effect of WBV therapy on the levels of serum serotonin in ovariectomized rats. MATERIALS AND METHODS: Thirty-six-month-old female Sprague Dawley rats weighing 276.15±37.75 g were ovariectomized to induce osteoporosis, and another ten rats underwent sham operation to establish sham control (SHAM) group. After 3 months, ovariectomized rats were divided into three subgroups and then separately treated with WBV, Alendronate (ALN) and normal saline (OVX), SHAM group was given normal saline. After 6 weeks of treatment, rats were sacrificed. Serum serotonin, RANKL, bone turnover markers, and bone mineral density (BMD), bone strength were evaluated. RESULTS: The serum serotonin level was significantly lower in WBV group than OVX and ALN groups (P<0.05 and P<0.001). RANKL levels significantly decreased in WBV and ALN groups compared to OVX group (P<0.001 for both). BMD and biomechanical parameters of femur significantly increased (P<0.05 for both) and bone turnover levels decreased (P<0.001 for both) in WBV group compared to OVX group. CONCLUSION: These data indicated that WBV enhanced the bone strength and BMD in ovariectomized rats most likely by reducing the levels of circulating serotonin.