Polycytosine RNA-binding protein 1 regulates osteoblast function via a ferroptosis pathway in type 2 diabetic osteoporosis.

BACKGROUND: Recently, type 2 diabetic osteoporosis (T2DOP) has become a research hotspot for the complications of diabetes, but the specific mechanism of its occurrence and development remains unknown. Ferroptosis caused by iron overload is con-sidered an important cause of T2DOP. Polycytosine RNA-binding protein 1 (PCBP1), an iron ion chaperone, is considered a protector of ferroptosis. AIM: To investigate the existence of ferroptosis and specific role of PCBP1 in the development of type 2 diabetes. METHODS: A cell counting kit-8 assay was used to detect changes in osteoblast viability under high glucose (HG) and/or ferroptosis inhibitors at different concentrations and times. Transmission electron microscopy was used to examine the morphological changes in the mitochondria of osteoblasts under HG, and western blotting was used to detect the expression levels of PCBP1, ferritin, and the ferroptosis-related protein glutathione peroxidase 4 (GPX4). A lentivirus silenced and overexpressed PCBP1. Western blotting was used to detect the expression levels of the osteoblast functional proteins osteoprotegerin (OPG) and osteocalcin (OCN), whereas flow cytometry was used to detect changes in reactive oxygen species (ROS) levels in each group. RESULTS: Under HG, the viability of osteoblasts was considerably decreased, the number of mitochondria undergoing atrophy was considerably increased, PCBP1 and ferritin expression levels were increased, and GPX4 expression was decreased. Western blotting results demonstrated that infection with lentivirus overexpressing PCBP1, increased the expression levels of ferritin, GPX4, OPG, and OCN, compared with the HG group. Flow cytometry results showed a reduction in ROS, and an opposite result was obtained after silencing PCBP1. CONCLUSION: PCBP1 may protect osteoblasts and reduce the harm caused by ferroptosis by promoting ferritin expression under a HG environment. Moreover, PCBP1 may be a potential therapeutic target for T2DOP.

Exosomes derived from platelet-rich plasma promote diabetic wound healing via the JAK2/STAT3 pathway.

Diabetic non-healing wounds are bringing a heavy burden on patients and society. Platelet-rich plasma (PRP) has been widely applied in tissue regenerating for containing various growth factors. Recently, PRP-derived exosomes (PRP-Exos) have been proved to be more effective than PRP in tissue regeneration. However, few studies have investigated the therapeutic potential of PRP-Exos in diabetic wound healing to date. Therefore, we extracted and identified exosomes derived from PRP and tested its promoting effect on diabetic wound healing in vivo and in vitro. We found that high glucose (HG) inhibited cell proliferation and migration and induced apoptosis through ROS-dependent activation of the JNK and p38 MAPK signaling pathways. PRP-Exos can stimulate fibroblast functions and accelerate diabetic wound healing. The benefits of PRP-Exos may be attributed to its capability to prevent HG-induced ROS-dependent apoptosis via the PDGF-BB/JAK2/STAT3/Bcl-2 signaling pathway. This illustrates the therapeutic potential of PRP-Exos in diabetic wounds.

ATF3 Regulates Osteogenic Function by Mediating Osteoblast Ferroptosis in Type 2 Diabetic Osteoporosis.

Purpose: Osteoporosis is a complication of type 2 diabetes, and it is characterized by reduced bone mass, augmented bone fragility, and increased risk of fracture, thus reducing patient quality of life, especially in the elderly. Ferroptosis has been implicated in the pathological process of type 2 diabetic osteoporosis (T2DOP), but the specific underlying mechanisms remain largely unknown. This study clarified the role of activating transcription factor 3 (ATF3) in T2DOP and explored its specific regulatory mechanism, providing a new treatment target for T2DOP. Methods: We cultured hFob1.19 cells in high glucose (HG, 35 mM) and knocked down ATF3 using short hairpin RNA (shRNA). We then measured cell viability, assessed morphology, quantified the expression of ATF3 and glutathione peroxidase 4 (GPX4), detected the levels of reactive oxygen species (ROS) and lipid peroxides, and determined the osteogenic function of osteoblasts. Cystine/glutamate antiporter (system Xc-) activity was evaluated by determining the expression of SLC7A11 and the levels of glutathione (GSH) and extracellular glutamate. We constructed a T2DOP rat model and observed the effect of ATF3 on ferroptosis and T2DOP by knocking down ATF3 using small interfering RNA (siRNA). Then, we evaluated the levels of iron metabolism, lipid peroxidation, and bone turnover in serum, detected the expression of ATF3, SLC7A11, and GPX4 in bone tissues, and assessed bone microstructure using microcomputed tomography. Results: ATF3 expression was increased in osteoblasts under HG condition and in T2DOP rats. Inhibiting the function of ATF3 increased GPX4 levels and reduced the accumulation of ROS and lipid peroxides. These changes inhibited the ferroptosis of osteoblasts and improved osteogenic function. In addition, HG induced ATF3 upregulation, resulting in decreased SLC7A11 expression and lower levels of intracellular GSH and extracellular glutamate. Conclusion: Osteoblast ferroptosis under HG conditions is induced by ATF3-mediated inhibition of system Xc- activity, and these events contribute to T2DOP pathogenesis.

Development and validation of a gene signature predicting the risk of postmenopausal osteoporosis.

AIMS: We aimed to develop a gene signature that predicts the occurrence of postmenopausal osteoporosis (PMOP) by studying its genetic mechanism. METHODS: Five datasets were obtained from the Gene Expression Omnibus database. Unsupervised consensus cluster analysis was used to determine new PMOP subtypes. To determine the central genes and the core modules related to PMOP, the weighted gene co-expression network analysis (WCGNA) was applied. Gene Ontology enrichment analysis was used to explore the biological processes underlying key genes. Logistic regression univariate analysis was used to screen for statistically significant variables. Two algorithms were used to select important PMOP-related genes. A logistic regression model was used to construct the PMOP-related gene profile. The receiver operating characteristic area under the curve, Harrell's concordance index, a calibration chart, and decision curve analysis were used to characterize PMOP-related genes. Then, quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the expression of the PMOP-related genes in the gene signature. RESULTS: We identified three PMOP-related subtypes and four core modules. The muscle system process, muscle contraction, and actin filament-based movement were more active in the hub genes. We obtained five feature genes related to PMOP. Our analysis verified that the gene signature had good predictive power and applicability. The outcomes of the GSE56815 cohort were found to be consistent with the results of the earlier studies. qRT-PCR results showed that RAB2A and FYCO1 were amplified in clinical samples. CONCLUSION: The PMOP-related gene signature we developed and verified can accurately predict the risk of PMOP in patients. These results can elucidate the molecular mechanism of RAB2A and FYCO1 underlying PMOP, and yield new and improved treatment strategies, ultimately helping PMOP monitoring.Cite this article: Bone Joint Res 2022;11(8):548-560.

Glycosaminoglycan-Based Hydrogel Delivery System Regulates the Wound Microenvironment to Rescue Chronic Wound Healing.

Chronic wounds cannot proceed through the normal, orderly, and timely sequence of repair. The adverse cycle between excess reactive oxide species (ROS) and a persistent inflammatory response is an important mechanism of impaired wound healing. Herein, by combining the intrinsic bioactivities of natural polysaccharides and natural drugs, a glycosaminoglycan-based hydrogel delivery system is proposed to regulate the wound microenvironment. Dynamic supramolecular cross-linking enables the hydrogel to easily encapsulate the drug and fully fill the wound area. As the backbone of the hydrogel, heparin captures inflammatory chemokines at the wound site, while hyaluronic acid mimics the function of ECM. The hydrophobic drug curcumin has been ingeniously encapsulated in the hydrogel through micellization, thereby exerting good ROS scavenging ability and anti-inflammatory activity. Evaluations in diabetic mice showed that this antioxidant and anti-inflammatory hydrogel was effective in reducing the influx of immune cells at the wound site and in down-regulating the inflammatory response. Accelerated wound healing was also observed, as evidenced by faster re-epithelialization and better ECM remodeling. The proposed hydrogel can regulate the microenvironment of wounds from multiple aspects and thereby achieve regression of wound repair, which may provide a new therapeutic strategy for chronic wounds.

ELAV-like RNA binding protein 1 regulates osteogenesis in diabetic osteoporosis: Involvement of divalent metal transporter 1.

Diabetic osteoporosis (DOP) is a complication of diabetes mellitus (DM) and occurs due to alterations in bone metabolism under hyperglycemic condition. ELAV-like RNA binding protein 1 (ELAVL1) is abnormally up-regulated in diabetes-related diseases. Bioinformatics prediction indicates that divalent metal transporter 1 (DMT1) is a potential target of ELAVL1. To explore the role of ELAVL1 and the involvement of ELAVL1/DMT1 axis in DOP, we established a mouse model of DM by administration of high-fat diet and intraperitoneal injection with streptozotocin (STZ). The expression of ELAVL1 and DMT1 was increased in the bone tissues of DM mice. Knockdown of ELAVL1 reduced iron level and oxidative stress, promoted osteogensis, and prevented bone mass loss, thus mitigating DOP in DM mice. In vitro, mouse pre-osteoblast MC3T3-E1 cells were treated with high glucose (25 mM) and ferric ammonium citrate (FAC, 200 µM). The inhibitory effects of ELAVL1 knockdown on iron accumulation and oxidative stress were evidenced in MC3T3-E1 cells. Knockdown of ELAVL1 enhanced osteoblast viability, differentiation and mineralization. Notably, the expression of DMT1 was positively correlated with that of ELAVL1 in vivo and in vitro. Overexpression of DMT1 abolished the effect of ELAVL1 knockdown on the behaviors of MC3T3-E1 cells, suggesting that ELAVL1 might function through regulating DMT1. In conclusion, knockdown of ELAVL1 likely alleviated DOP by inhibiting iron overload and oxidative stress and promoting osteogenesis, and DMT1 might be involved in this process. These findings provide insights into the pathogenesis of DOP and suggest a potential therapeutic target for DOP treatment.

Effect of tourniquet application on postoperative outcomes in sinus tarsi approach for intra-articular calcaneus fractures.

INTRODUCTION: Tourniquets are commonly used during foot and ankle surgery to provide a bloodless operative field and increase surgical comfort, despite the potential risks associated with it. This study compared postoperative outcomes of tourniquet-assisted and non-tourniquet-assisted operative fixation of calcaneal fractures via the sinus tarsi approach. MATERIALS AND METHODS: A retrospective study from March 2015 to December 2018 revealed 131 patients with closed calcaneal fractures who underwent minimally invasive surgery at our hospital. Visualization, operating time, blood loss, and postoperative pain were collected. Patients in the tourniquet group (n = 62) were compared with patients in the non-tourniquet group (n = 69). RESULTS: The visibility of the surgical field was fair/poor in 2 cases in the tourniquet group and fair/poor in 19 cases in the non-tourniquet group (P < 0.05). The mean operative time was 64.7 ± 3.5 min in the tourniquet group and 76.0 ± 6.1 min in the non-tourniquet group (P < 0.05). The estimated intraoperative and postoperative blood loss was 56.6 ± 33.3 and 100.0 ± 25.3 mL, respectively, in the tourniquet group and 205.0 ± 31.6 and 38.3 ± 19.8 mL, respectively, in the non-tourniquet group (P < 0.05). The VAS pain scores 24 h, 48 h, and 72 h postoperatively were 4.3 ± 1.8, 3.1 ± 1.2, and 2.0 ± 0.5 points, respectively, in the tourniquet group and 2.1 ± 1.1, 1.6 ± 1.0, and 1.0 ± 0.3 points, respectively, in the non-tourniquet group (P < 0.05). CONCLUSION: Tourniquet application during the sinus tarsi approach for calcaneal fractures can significantly improve surgical visualization and reduce intraoperative blood loss. However, adverse events associated with the use of tourniquets include increased postoperative pain and bleeding. Due to increased postoperative bleeding and pain, more attention should be given to the postoperative phase in patients treated with tourniquets.

Mitochondrial Ferritin Deficiency Promotes Osteoblastic Ferroptosis Via Mitophagy in Type 2 Diabetic Osteoporosis.

The incidence of type 2 diabetic osteoporosis (T2DOP), which seriously threatens elderly people's health, is rapidly increasing in recent years. However, the specific mechanism of the T2DOP is still unclear. Studies have shown the relationship between iron overload and T2DOP. Mitochondrial ferritin (FtMt) is a protein that stores iron ions and intercepts toxic ferrous ions in cells mitochondria. Ferroptosis, an iron-dependent cell injured way, may be related to the pathogenesis of T2DOP. In this study, we intend to elucidate the effect of FtMt on ferroptosis in osteoblasts and explain the possible mechanism. We first detected the occurrence of ferroptosis in bone tissue and the expression of FtMt after inducing T2DOP rat model. Then we used hFOB1.19 cells to study the influence of high glucose on FtMt, ferroptosis, and osteogenic function of osteoblasts. Then we observed the effect of FtMt on ferroptosis and osteoblast function by lentiviral silencing and overexpression of FtMt. We found ferroptosis in T2DOP rats bone. Overexpression of FtMt reduced osteoblastic ferroptosis under high glucose condition while silent FtMt induced mitophagy through ROS / PINK1/Parkin pathway. Then we found increased ferroptosis in osteoblasts after activating mitophagy by carbonyl cyanide-m-chlorophenyl-hydrazine (CCCP, a mitophagy agonist). Our study demonstrated that FtMt inhibited the occurrence of ferroptosis in osteoblasts by reducing oxidative stress caused by excess ferrous ions, and FtMt deficiency induced mitophagy in the pathogenesis of T2DOP. This study suggested that FtMt might serve as a potential target for T2DOP therapy.

Host Phylogeny and Diet Shape Gut Microbial Communities Within Bamboo-Feeding Insects.

The gut microbiome plays an important role in a host's development and adaption to its dietary niche. In this study, a group of bamboo-feeding insects are used to explore the potential role of the gut microbiota in the convergent adaptation to extreme diet specialization. Specifically, using a 16S rRNA marker and an Illumina sequencing platform, we profiled the microbial communities of 76 gut samples collected from nine bamboo-feeding insects, including both hemimetabolous (Orthoptera and Hemiptera) and holometabolous (Coleoptera and Lepidoptera) species, which are specialized in three distinct dietary niches: bamboo leaf, shoot, and sap. The gut microbiota of these insects were dominated by Proteobacteria, Firmicutes, and Bacteroidetes and were clustered into solid (leaf and shoot) and liquid (sap) dietary niches. The gut bacterial communities of insects feeding on solid diet overlapped significantly, even though these insects belong to phylogenetically distant lineages representing different orders. In addition, the presence of cellulolytic bacterial communities within the gut microbiota allows bamboo-feeding insects to adapt to a highly specialized, fiber-rich diet. Although both phylogeny and diet can impact the structure and composition of gut microbiomes, phylogeny is the primary driving force underlying the convergent adaptation to a highly specialized diet, especially when the related insect species harbor similar gut microbiomes and share the same dietary niche over evolutionary timescales. These combined findings lay the foundation for future research on how convergent feeding strategies impact the interplays between hosts and their gut microbiomes and how the gut microbiota may facilitate convergent evolution in phylogenetically distant species in adaptation to the shared diet.

Pseudomyogenic Hemangioendothelioma of the Talocalcaneal Coalition: A Case Report.

Pseudomyogenic hemangioendothelioma is a rare soft tissue tumor most often found in the lower extremities and predominantly occurring in males. The talocalcaneal coalition is an anatomic anomaly that develops between the talus and calcaneus bones, can cause hindfoot pain and subtalar joint stiffness, and has a prevalence of less than 1%. We present what is to our knowledge the first case report of a 17-year-old male with pseudomyogenic hemangioendothelioma occurring within a talocalcaneal coalition. The patient was treated with local excision of the tumor and the coalition. His American Orthopaedic Foot & Ankle Society ankle/hindfoot score went from 70 preoperatively to 92 at 1 year postoperatively, and he has had no evidence of recurrence at 1 and 3 years postoperatively. These tumors have suggestive but not diagnostic computed tomography, magnetic resonance imaging, and histopathological findings, and they are associated with a uniquely characteristic immunophenotype, including immunochemical reactivity to CD31, FLi-1, INI-1, ERG, and FOSB. Primary treatment of pseudomyogenic hemangioendothelioma most often involves local excision (but can require amputation) and may include adjuvant radiotherapy and/or chemotherapy. It has a relatively favorable prognosis, with a moderate risk of local recurrence and a low risk of metastases. Because metastases have been reported many years after treatment, long-term follow-up is necessary.

Acid Sphingomyelinase and Acid ß-Glucosidase 1 Exert Opposite Effects on Interleukin-1ß-Induced Interleukin 6 Production in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

Acid sphingomyelinase (ASM) and acid ß-glucosidase 1 (GBA1) catalyze ceramide formation through different routes, and both are involved in rheumatoid arthritis (RA) pathogenesis as well as IL-6 production. However, whether ASM and GBA1 regulate IL-6 production in RA remains unknown. Serum ASM, GBA1, and ceramide levels were measured in RA patients and healthy controls by enzyme-linked immunosorbent assay, and their correlations with clinical indicators of patients were evaluated. Pharmacologic inhibitors or small hairpin RNAs of ASM and GBA1 were employed to explore the roles of ASM and GBA1 in IL-6 production, cell behavior, and MAPK signaling in fibroblast-like synoviocytes from RA patients (RAFLS). ASM, GBA1, and ceramide serum levels were significantly elevated in patients with RA. GBA1 and ceramide serum levels were negatively and positively correlated with IL-6 serum level in RA patients, respectively. ASM inhibitor or knockdown of ASM abolished IL-1ß-induced IL-6 expression and secretion. Functionally, ASM inhibitor suppressed IL-1ß-induced cell proliferation, migration, and invasion in RAFLS. Mechanistically, ASM inhibitor or knockdown of ASM effectively countered IL-1ß-induced activation of p38 MAPK signaling. The pharmacologic inhibitor or knockdown of GBA1 exhibited the opposite effects. Importantly, p38 inhibitor blocked IL-1ß-induced IL-6 production in RAFLS. ASM plays a pathogenic role in RA, whereas GBA1 plays a protective role in RA possibly by regulating IL-6 production in RAFLS at least partially via p38 signaling, serving as potential therapeutic targets in RA treatment.

Open Curettage With Bone Augmentation for Symptomatic Tumors and Tumor-like Lesions of Calcaneus: A Comparison of Bioactive Glass Versus Allogeneic Bone.

Few studies have characterized the clinical outcomes of 45S5 Bioglass® applied as a bone graft to that of allogeneic bone applied in calcaneal open curettage. Therefore, the purpose of the present investigation was to compare the outcomes of patients with calcaneal tumors and tumor-like lesions treated by open curettage with 45S5 Bioglass® or allogeneic bone. Of the 31 patients who underwent open curettage (18 cases of unicameral bone cysts, 7 cases of aneurysmal bone cysts, and 6 cases of intraosseous lipoma), 16 (52%) received grafts with 45S5 Bioglass® and 15 (48%) with allogeneic bone. All the feet achieved bone fusion according to the modified Neer radiographic classification system at the last follow-up examination. The mean bone ingrowth time for the grafts with 45S5 Bioglass® versus allogeneic bone was 3.71 ± 0.86 versus 4.46 ± 1.04 months (p = .038), the mean bone healing time was 4.86 ± 0.93 versus 5.73 ± 1.07 months (p = .021), and the mean incision drying time was 7.2 ± 1.8 versus 8.2 ± 1.5 days (p = .047), respectively. No differences were found in the postoperative American Orthopaedic Foot and Ankle Society ankle-hindfoot scale scores between the 2 groups (p = .213). These results show that 45S5 Bioglass® can better facilitate the formation of new bone with a faster drying time of the incision than allogeneic bone. Although both materials can benefit the clinical outcomes of calcaneal tumors and tumor-like lesions, further studies are needed to observe the long-term complications and lesion recurrence rates.

Melatonin Suppresses Ferroptosis Induced by High Glucose via Activation of the Nrf2/HO-1 Signaling Pathway in Type 2 Diabetic Osteoporosis.

Ferroptosis is recently identified, an iron- and reactive oxygen species- (ROS-) dependent form of regulated cell death. This study was designed to determine the existence of ferroptosis in the pathogenesis of type 2 diabetic osteoporosis and confirm that melatonin can inhibit the ferroptosis of osteoblasts through activating Nrf2/HO-1 signaling pathway to improve bone microstructure in vivo and in vitro. We treated MC3T3-E1 cells with different concentrations of melatonin (1, 10, or 100 µM) and exposed them to high glucose (25.5 mM) for 48 h in vitro. Our data showed that high glucose can induce osteoblast cytotoxicity and the accumulation of lipid peroxide, the mitochondria of osteoblast show the same morphology changes as the erastin treatment group, and the expression of ferroptosis-related proteins glutathione peroxidase 4 (GPX4) and cystine-glutamate antiporter (SLC7A11) is downregulated, but these effects were reversed by ferroptosis inhibitor ferrastatin-1 and iron chelator deferoxamine (DFO). Furthermore, western blot and real-time polymerase chain reaction were used to detect the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1); osteogenic capacity was evaluated by alizarin red S staining and the expression of osteoprotegerin, osteocalcin, and alkaline phosphatase; the results showed that the expression levels of these proteins in osteoblasts with 1, 10, or 100 µM melatonins were significantly higher than the high glucose group, but after using Nrf2-SiRNA interference, the therapeutic effect of melatonin was significantly inhibited. We also performed in vivo experiments in a diabetic rat model treated with two concentrations of melatonin (10, 50 mg/kg). Dynamic bone histomorphometry and micro-CT were used to observe the rat bone microstructure, and the expression of GPX4 and Nrf2 was determined by immunohistochemistry. Here, we first report that high glucose induces ferroptosis via increased ROS/lipid peroxidation/glutathione depletion in type 2 diabetic osteoporosis. More importantly, melatonin significantly reduced the level of ferroptosis and improved the osteogenic capacity of MC3T3-E1 through activating the Nrf2/HO-1 pathway in vivo and in vitro.

Surgical Management of Monoarticular Rheumatoid Arthritis of the Fifth Metatarsophalangeal Joint.

OBJECTIVE: To investigate the clinical and radiological outcomes in patients with monoarticular rheumatoid arthritis of the fifth metatarsophalangeal joint after Weil osteotomy. METHODS: From July 2011 to September 2015, 18 feet of 16 rheumatoid arthritis patients who underwent Weil osteotomy of the fifth metatarsal toe with a mean age at the time of surgery of 48.8 ± 7.4 years were reviewed retrospectively. The mean disease duration was 44.6 ± 6.8 months, and the follow-up period was 36 months. Clinical outcomes were evaluated according to the American Orthopaedic Foot and Ankle Society lesser metatarsophalangeal interphalangeal scale (AOFAS), 10-item SF-36 physical functioning and 2-item SF-36 bodily pain, Visual Analogue Scale (VAS), and satisfaction scores. In the radiologic evaluation, fifth metatarsophalangeal angle (MTP-5), lateral deviation angle (LDA), and longitudinal axes of the fifth metatarsal were measured on anterior-posterior (AP) weight-bearing radiographs preoperative and at the last follow-up. RESULTS: Clinical assessment showed that the total average of AOFAS was significantly increased from preoperative 53.6 ± 9.0 to 98.7 ± 2.0 points, and the VAS score was significantly decreased from preoperative 4.1 ± 1.5 to 1.1 ± 0.8 points at the last follow-up (P < 0.001). The total averages of SF-36 physical functioning and SF-36 bodily pain were significantly increased from preoperative 48.9 ± 9.0 to 99. ± 2.1 and from 61.4 ± 12.1 to 99.4 ± 2.4 points, respectively, at the last follow-up (P < 0.001). Subjectively, the excellent outcome of the surgery results were rated by 13 patients (81.3%) that underwent surgery and three patients (18.7%) were rated as good. Regarding radiographic parameters, the mean MTP-5 significantly decreased from 21.5° ± 1.2° preoperatively to 10.2° ± 1.2°, the mean LDA significantly decreased from 7.1° ± 1.2° preoperatively to -2.4° ± 1.0°, and the mean length of the fifth metatarsal was significantly shortened from 71.5 ± 1.4 preoperatively to 67.8 ± 1.5 mm at the final follow-up visit (P < 0.001). No malunion, nonunion, necrosis, pseudoarthrosis, or fracture of the fifth metatarsal was found. No exuberant bone growth, perforation of the screw, subluxation, or dislocation was observed. No indications of modification, revision or repeat surgery, or delayed wound healing were observed during follow-up period. CONCLUSION: Surgical management of the monoarticular rheumatoid arthritis of the fifth metatarsophalangeal joint can achieve good clinical and radiological outcomes, with pain relief and dislocation reduction, as well as high satisfaction and improvement without recurrence or progression during the follow-up period.

NIPA2 regulates osteoblast function by modulating mitophagy in type 2 diabetes osteoporosis.

The highly selective magnesium transporter non-imprinted in Prader-Willi/Angelman syndrome region protein 2 (NIPA2) has recently been associated with the development and progression of type 2 diabetes osteoporosis, but the mechanisms involved are still poorly understood. Because mitophagy is involved in the pathology of type 2 diabetes osteoporosis, the present study aimed to explore the relationship among NIPA2, mitophagy and osteoblast osteogenic capacity. NIPA2 expression was reduced in C57BKS background db/db mice and in vitro models of type 2 diabetes osteoporosis, and the activation of mitophagy in primary culture osteoblast-derived from db/db mice and in high glucose-treated human fetal osteoblastic cells (hFOB1.19) was observed. Knockdown, overexpression of NIPA2 and pharmacological inhibition of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) showed that NIPA2 increased osteoblast function, which was likely regulated by PTEN induced kinase 1 (PINK1)/E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy via the PGC-1α/forkhead box O3a(FoxO3a)/mitochondrial membrane potential (MMP) pathway. Furthermore, the negative effect of mitophagy on osteoblast function was confirmed by pharmacological regulation of mitophagy and knockdown of Parkin. Taken together, these results suggest that NIPA2 positively regulates the osteogenic capacity of osteoblasts via the mitophagy pathway in type 2 diabetes.

Chinese Consensus on Insertional Achilles Tendinopathy.

BACKGROUND: Insertional Achilles tendinopathy (IAT) is a common finding in the clinic. However, consensus on its mechanism, pathological process, diagnosis, treatment, and rehabilitation is lacking. Thus, the Chinese Society of Sports Medicine organized and invited experts representing the fields of ankle disease and tendinopathy to jointly develop an expert consensus on IAT. STUDY DESIGN: A consensus statement of the Chinese Society of Sports Medicine. METHODS: A total of 34 experts in the field of sports medicine and orthopaedics were invited to participate in the compilation of a consensus statement regarding IAT. Consensus was achieved according to the Delphi method. First, 10 working groups composed of 34 experts were established to compile draft statements about clinical problems related to IAT by reviewing and analyzing the available literature. An expert consensus meeting to discuss drafts was then arranged. Each statement was individually presented and discussed, followed by a secret vote. Consensus was reached when more than 50% of the experts voted in its favor. The strength of the proposed recommendation was classified based on the proportion of favorable votes: consensus, 51% to 74%; strong consensus, 75% to 99%; unanimity, 100%. RESULTS: Of the 10 expert consensus statements on the clinical diagnosis and treatment of IAT, there was strong consensus for 8 statements and unanimity for 2 statements. CONCLUSION: This expert consensus focused on the concepts, causes, pathological process, clinical diagnosis, and treatment of IAT. Accepted recommendations in these areas which will assist clinicians in carrying out standardized management of related diseases.

NIPA2 regulates osteoblast function via its effect on apoptosis pathways in type 2 diabetes osteoporosis.

Type 2 diabetes osteoporosis has recently become a hot topic in the study of diabetic complications, but the specific mechanism of its development remains unclear. Non-imprinted in Prader-Willi/Angelman syndrome region protein 2 (NIPA2), a highly-selective magnesium ion transporter, has been found to be associated with type 2 diabetes. In this study we aimed to investigate the specific role and mechanism of NIPA2 in the pathogenesis of type 2 diabetes osteoporosis. We first used western blotting, PCR, immunofluorescence, and magnesium ion probes to detect changes of NIPA2 and intracellular magnesium levels in osteoblasts at different concentrations of advanced glycation end products (AGEs). We then up- or down-regulated NIPA2 using a lentivirus and analyzed apoptotic biomarkers as well as the osteogenic ability of osteoblasts. We found that AGEs dose-dependently down-regulated the expression of NIPA2 in osteoblasts. NIPA2 also regulated osteoblast apoptosis by affecting the intracellular magnesium level and further affecting the osteogenic capacity of osteoblasts. Our study revealed the changes of NIPA2 in response to AGEs in the environment, as well as its function and mechanism in osteoblasts, demonstrating its important role in the pathogenesis of type 2 diabetes osteoporosis. The study suggests that NIPA2 is a potential target for the treatment of type 2 diabetes osteoporosis.

Autophagy alleviates the decrease in proliferation of amyloid ß1­42­treated bone marrow mesenchymal stem cells via the AKT/mTOR signaling pathway.

Alzheimer's disease (AD) and osteoporosis (OP) are 2 common progressive age­associated diseases, primarily affecting the elderly worldwide. Accumulating evidence has demonstrated that patients with AD are more likely to suffer from bone mass loss and even OP, but whether it is a pathological feature of AD or secondary to motor dysfunction remains poorly understood. The present study aimed to investigate whether amyloid­ß1­42 (Aß1­42), the typical pathological product of AD, exhibited a negative effect on the proliferation of bone marrow mesenchymal stem cells (BMSCs) and the role of autophagy. The proliferation of BMSCs was measured using a Cell Counting Kit­8 assay, cell cycle analysis and 5­ethynyl­2'­deoxyuridine (EdU) staining. The autophagy­associated proteins microtubule­associated proteins 1A/1B light chain 3B and sequestosome 1 (p62) were evaluated by western blot analysis and autophagosomes were detected by transmission electron microscopy and immunofluorescence. The activity of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway was measured using western blot analysis, and the autophagy inducer rapamycin (RAPA), inhibitor 3­methyladenine (3­MA) and the AKT activator SC79 were also used to investigate the role of AKT/mTOR signaling pathway and autophagy in the proliferation of BMSCs. The results suggested that the proliferation of BMSCs treated with Aß1­42 was inhibited, with the autophagy level increasing following treatment with Aß1­42 in a dose­dependent manner, while the AKT/mTOR signaling pathway participated in the regulation of the autophagy level. Activation of autophagy using RAPA inhibited the decrease in proliferation of BMSCs, while suppression of autophagy by 3­MA and activation of the AKT/mTOR signaling pathway increased the decrease in proliferation of BMSCs caused by Aß1­42. It was concluded that Aß1­42, as an external stimulus, suppressed the proliferation of BMSCs directly and that the AKT/mTOR signaling pathway participated in the regulation of the level of autophagy. Concomitantly, autophagy may serve as a resistance mechanism in inhibiting the decreased proliferation of BMSCs treated with Aß1­42.

Early initiation of zoledronic acid does not impact bone healing or clinical outcomes of hallux valgus orthomorphia.

Objective This prospective randomized controlled study was performed to determine whether early drug use for osteoporosis impacts bone healing after orthomorphic surgery for hallux valgus (HV) in menopausal patients with osteoporosis. Methods This study included 113 consecutive patients with osteoporosis who underwent a combination of Lapidus arthrodesis and Akin osteotomy for treatment of HV. The patients were randomly divided into a zoledronic acid (ZOL) group (5-mg intravenous injection of ZOL, n = 56) and a placebo group (n = 57); both ZOL and placebo were administered 1 week postoperatively. Radiographs were taken preoperatively and at 1, 6, 8, 10, and 12 weeks postoperatively to record the time of the first tarsometatarsal joint (FTJ) fusion and Akin osteotomy site healing. Clinical outcomes were evaluated using the American Orthopedic Foot and Ankle Society (AOFAS) scoring system 24 weeks after surgery. Results There were no statistically significant differences in the FTJ fusion time after Lapidus arthrodesis, healing time after Akin osteotomy, or postoperative AOFAS scores between the two groups. Conclusion Early initiation of ZOL does not impact the bone healing or clinical outcomes of orthomorphic surgery for HV in postmenopausal women diagnosed with osteoporosis after a combination of Lapidus arthrodesis and Akin osteotomy.

High glucose downregulates the effects of autophagy on osteoclastogenesis via the AMPK/mTOR/ULK1 pathway.

Diabetes is a chronic disease that disrupts the balance between bone formation and bone desorption, which can lead to osteoporosis, increasing the risk of fracture. However, compared with osteoblasts, the biological effects of hyperglycemia on osteoclastogenesis remain to be elucidated. Therefore, we investigated the impact of glucose at different concentrations (5.5, 10.5, 15.5, 20.5, 25.5, and 30.5 mM) on osteoclastogenesis using RAW264.7 cells. Cell proliferation was measured with the cell counting kit-8 assay, and osteoclastogenesis was detected with tartrate-resistant acid phosphatase staining and bone resorption assays, as well as protein cathepsin K expression. Compound C, the AMP-activated protein kinase (AMPK) pathway inhibitor, was used to examine the relationship between the AMPK/mTOR/ULK1 signaling pathway and autophagy in osteoclasts. Autophagy was evaluated with transmission electron microscopy and immunofluorescence microscopy and associated proteins were detected with western blotting. The pharmacological autophagic reagents bafilomycin A1, 3-methyladenine, and rapamycin were used to determine the effect of autophagy on osteoclastogenesis. Our results showed that glucose negatively affected osteoclast formation and function but did not affect the proliferation of RAW264.7 cells. Suppression of the AMPK/mTOR/ULK1 signaling axis decreased autophagy in glucose-mediated osteoclast. Furthermore, High levels of glucose decreased autophagy level in osteoclasts. Additionally, interfering with autophagy affected osteoclast formation and function. These findings clarify the mechanisms underlying the effects of glucose-mediated osteoclastogenesis and will help identify novel therapeutic strategies for the protection of skeletal health in diabetic osteoporosis.