IMPC-based screening revealed that ROBO1 can regulate osteoporosis by inhibiting osteogenic differentiation.

Introduction: The utilization of denosumab in treating osteoporosis highlights promising prospects for osteoporosis intervention guided by gene targets. While omics-based research into osteoporosis pathogenesis yields a plethora of potential gene targets for clinical transformation, identifying effective gene targets has posed challenges. Methods: We first queried the omics data of osteoporosis clinical samples on PubMed, used International Mouse Phenotyping Consortium (IMPC) to screen differentially expressed genes, and conducted preliminary functional verification of candidate genes in human Saos2 cells through osteogenic differentiation and mineralization experiments. We then selected the candidate genes with the most significant effects on osteogenic differentiation and further verified the osteogenic differentiation and mineralization functions in mouse 3T3-E1 and bone marrow mesenchymal stem cells (BMSC). Finally, we used RNA-seq to explore the regulation of osteogenesis by the target gene. Results: We identified PPP2R2A, RRBP1, HSPB6, SLC22A15, ADAMTS4, ATP8B1, CTNNB1, ROBO1, and EFR3B, which may contribute to osteoporosis. ROBO1 was the most significant regulator of osteogenesis in both human and mouse osteoblast. The inhibitory effect of Robo1 knockdown on osteogenic differentiation may be related to the activation of inflammatory signaling pathways. Conclusion: Our study provides several novel molecular mechanisms involved in the pathogenesis of osteoporosis. ROBO1 is a potential target for osteoporosis intervention.

An updated overview of the search for biomarkers of osteoporosis based on human proteomics.

Osteoporosis is a chronic metabolic disease that increases bone fragility and, leads to severe osteoporotic fractures. In recent years, the use of high-throughput omics to explore physiological and pathological biomarkers related to bone metabolism has gained popularity. In this review, we first briefly review the technical approaches of proteomics. Additionally, we summarize the relevant literature in the last decade to provide a comprehensive overview of advances in human proteomics related to osteoporosis. We describe the specific roles of various proteins related to human bone metabolism, highlighting their potential as biomarkers for risk assessment, early diagnosis and disease course monitoring in osteoporosis. Finally, we outline the main challenges currently faced by human proteomics in the field of osteoporosis and offer suggestions to address these challenges, to inspire the search for novel osteoporosis biomarkers and a foundation for their clinical translation. In conclusion, proteomics is a powerful tool for discovering osteoporosis-related biomarkers, which can not only provide risk assessment, early diagnosis and disease course monitoring, but also reveal the underlying mechanisms of disease and provide key information for personalized treatment. The translational potential of this article: This review provides an insightful summary of recent human-based studies on osteoporosis-associated proteomics, which can aid the search for novel osteoporosis biomarkers based on human proteomics and the clinical translation of research results.

Diagnosis and treatment of anterior cruciate ligament injuries: Consensus of Chinese experts part II: Graft selection and clinical outcome evaluation.

Background: In the recent decade, there has been substantial progress in the technologies and philosophies associated with diagnosing and treating anterior cruciate ligament (ACL) injuries in China. The therapeutic efficacy of ACL reconstruction in re-establishing the stability of the knee joint has garnered widespread acknowledgment. However, the path toward standardizing diagnostic and treatment protocols remains to be further developed and refined. Objective: In this context, the Chinese Association of Orthopaedic Surgeons (CAOS) and the Chinese Society of Sports Medicine (CSSM) collaboratively developed an expert consensus on diagnosing and treating ACL injury, aiming to enhance medical quality through refining professional standards. Methods: The consensus drafting team invited experts across the Greater China region, including the mainland, Hong Kong, Macau, and Taiwan, to formulate and review the consensus using a modified Delphi method as a standardization approach. As members of the CSSM Lower Limb Study Group and the CAOS Arthroscopy and Sports Medicine Study Group, invited experts concentrated on two pivotal issues: "Graft Selection" and "Clinical Outcome Evaluation" during the second part of the consensus development. Results: This focused discussion ultimately led to a strong consensus on nine specific consensus terms. Conclusion: The consensus clearly states that ACL reconstruction has no definitive "gold standard" graft choice. Autografts have advantages in healing capability but are limited in availability and have potential donor site morbidities; allografts reduce surgical trauma but incur additional costs, and there are concerns about slow healing, quality control issues, and a higher failure rate in young athletes; synthetic ligaments allow for early rehabilitation and fast return to sport, but the surgery is technically demanding and incurs additional costs. When choosing a graft, one should comprehensively consider the graft's characteristics, the doctor's technical ability, and the patient's needs. When evaluating clinical outcomes, it is essential to ensure an adequate sample size and follow-up rate, and the research should include patient subjective scoring, joint function and stability, complications, surgical failure, and the return to sport results. Medium and long-term follow-ups should not overlook the assessment of knee osteoarthritis.

The influence of body fat content and distribution on bone mass in healthy Chinese adults.

Background: Previous studies have reported a close relationship between body mass index (BMI) and bone mineral density (BMD). However, the effects of fat on bone mass remain controversial, particularly for fat tissue distribution. The aim of this study was to evaluate the association between regional fat percentage and BMD using a population-based database. Methods: This study included participants who were referred to the Department of Radio Diagnosis for dual-energy X-ray absorptiometry (DEXA) scan from January 2018 to December 2020. The relationships between BMI and regional fat percentage with BMD were assessed using multiple linear regression and generalized additive models. The risk of low bone mass was determined using logistic regression. Results: There was a negative relationship between the regional fat percentage and femoral neck BMD (FN BMD) or lumbar spine BMD (LS BMD) in both genders (p < 0.05). In females, an inverted U-shaped relationship was observed between regional fat percentage and BMD at both the femoral neck and lumbar spine. The impact of trunk fat percentage on LS BMD was associated with the highest OR of low bone mass in females (OR 3.1, 95% CI 2.6 to 3.7, p for trend <0.001), while the impact of abdomen fat percentage on FN BMD was associated with the highest OR of low bone mass in males (OR 2.2, 95% CI 1.8 to 2.7, p for trend <0.001). Conclusion: There was an inverted U-shaped relationship between regional fat percentage and BMD. Excessive regional fat percentage may be harmful to bone health in both genders. To promote bone health, males should restrict their abdomen circumference and avoid abdominal adiposity, while females should control their trunk circumference.

Vertebral HU value and the pectoral muscle index based on chest CT can be used to opportunistically screen for osteoporosis.

BACKGROUND: Existing studies have shown that computed tomography (CT) attenuation and skeletal muscle tissue are strongly associated with osteoporosis; however, few studies have examined whether vertebral HU values and the pectoral muscle index (PMI) measured at the level of the 4th thoracic vertebra (T4) are strongly associated with bone mineral density (BMD). In this study, we demonstrate that vertebral HU values and the PMI based on chest CT can be used to opportunistically screen for osteoporosis and reduce fracture risk through prompt treatment. METHODS: We retrospectively evaluated 1000 patients who underwent chest CT and DXA scans from August 2020-2022. The T4 HU value and PMI were obtained using manual chest CT measurements. The participants were classified into normal, osteopenia, and osteoporosis groups based on the results of dual-energy X-ray (DXA) absorptiometry. We compared the clinical baseline data, T4 HU value, and PMI between the three groups of patients and analyzed the correlation between the T4 HU value, PMI, and BMD to further evaluate the diagnostic efficacy of the T4 HU value and PMI for patients with low BMD and osteoporosis. RESULTS: The study ultimately enrolled 469 participants. The T4 HU value and PMI had a high screening capacity for both low BMD and osteoporosis. The combined diagnostic model-incorporating sex, age, BMI, T4 HU value, and PMI-demonstrated the best diagnostic efficacy, with areas under the receiver operating characteristic curve (AUC) of 0.887 and 0.892 for identifying low BMD and osteoporosis, respectively. CONCLUSIONS: The measurement of T4 HU value and PMI on chest CT can be used as an opportunistic screening tool for osteoporosis with excellent diagnostic efficacy. This approach allows the early prevention of osteoporotic fractures via the timely screening of individuals at high risk of osteoporosis without requiring additional radiation.

The paradox of bone mineral density and fracture risk in type 2 diabetes.

Fracture risk in type 2 diabetes (T2D) patients is paradoxically increased despite no decrease in areal bone mineral density (BMD). This phenomenon, known as the "diabetic bone paradox", has been attributed to various factors including alterations in bone microarchitecture and composition, hyperinsulinemia and hyperglycemia, advanced glycation end products (AGEs), and comorbidities associated with T2D. Zhao et al. recently investigated the relationship between T2D and fracture risk using both genetic and phenotypic datasets. Their findings suggest that genetically predicted T2D is associated with higher BMD and lower fracture risk, indicating that the bone paradox is not observed when confounding factors are controlled using Mendelian randomization (MR) analysis. However, in prospective phenotypic analysis, T2D remained associated with higher BMD and higher fracture risk, even after adjusting for confounding factors. Stratified analysis revealed that the bone paradox may disappear when T2D-related risk factors are eliminated. The study also highlighted the role of obesity in the relationship between T2D and fracture risk, with BMI mediating a significant portion of the protective effect. Overall, managing T2D-related risk factors may be crucial in preventing fracture risk in T2D patients.

Analysis of the clinical characteristics and risk factors associated with contralateral hip fracture after initial hip fracture in elderly patients: a retrospective cohort study.

Fractures of the contralateral hip may easily occur in elderly patients after an initial hip fracture. The aim of this study was to investigate the clinical characteristics and major predisposing risk factors of contralateral hip fracture after initial hip fracture in the elderly, to provide a clinical basis for preventing contralateral hip fracture. The data of 1586 patients who had sustained first or second hip fractures and had been surgically treated in our department were retrospectively analyzed. Potential predictive factors for contralateral hip fracture and descriptive statistics associated with surgery (such as blood loss, operation time, and length of hospital stay) were recorded. Of these patients, 133 (8.4%) suffered contralateral hip fracture. The rates of contralateral fracture after femoral neck and intertrochanteric fracture were 5.4% and 10.7% respectively (P < 0.01). Fifty-four cases of contralateral hip fracture occurred within one year, an incidence of 40.6%, while 95 cases (71.4%) and 105 cases (78.9%) occurred within two and three years, respectively, with a interval duration of 21.6 months. The risk factors for contralateral hip fracture were found to be age, type of first fracture, bone mineral density, the Singh index, and concomitant internal medical diseases, which were found to be significantly associated with an increased risk of contralateral hip fracture in multivariate logistic regression analysis (P < 0.05). In conclusion, the presence of concomitant internal diseases, type of first fracture, bone mineral density, the Singh index, and age were found to be significant predictors of the risk of contralateral hip fracture in elderly patients after a first hip fracture.

The femoral anterior tangent line could serve as a reliable alternative reference axis for distal femoral rotational alignment in total knee arthroplasty: an MRI-based study.

Background: This study aimed to evaluate the reference value of the femoral anterior tangent (FAT) line as a guidance of distal femoral rotation on magnetic resonance images (MRI). Methods: We retrospectively included 81 patients (106 knees) diagnosed as ailing from primary knee osteoarthritis. The indirect rotational axes including the FAT line, the perpendicular line to the anteroposterior axis (pAPA), and the posterior condylar axis (PCA) were identified on MRI, and their angles related to the clinical transepicondylar axis (cTEA) or surgical transepicondylar axis (sTEA) were measured. The patients were further divided into subgroups according to the Kellgren-Lawrence (K-L) grades, the joint-line convergence angle (JLCA), and the arithmetic hip-knee-ankle angle (aHKA) to assess the variance of different rotational reference axes. Results: The FAT line was -11.8° ± 3.6° internally rotated to the cTEA and -7.5° ± 3.6° internally rotated to the sTEA. The FAT/cTEA angle and the FAT/sTEA angle shared a similar frequency distribution pattern but a little greater variance to the pAPA/cTEA angle and the PCA/cTEA angle. The PCA/cTEA angle in the JLCA |x| ≥ 6° subgroup was significantly smaller than in the two other JLCA subgroups. The pAPA/cTEA angle and the PCA/cTEA angle also presented statistical significance within the aHKA subgroups. While the FAT/cTEA angle and the FAT/sTEA angle demonstrated superior stability among the different K-L grades, JLCA subgroups, and aHKA subgroups. Conclusion: The FAT line was less affected by the degree of knee osteoarthritis and lower limb alignment, which could serve as a reliable alternative reference axis for the distal femoral rotational alignment in total knee arthroplasty.

Molecular epidemiological characteristics of osteoarthritis-associated Brucella melitensis in China: evidence from whole-genome sequencing-based analysis.

BACKGROUND: Brucellosis, developing complications including arthritis, spondylitis, sacroiliitis, and osteomyelitis, is one of the most common zoonotic diseases in the current world which causes economic losses to the livestock industry and is a great public health concern. Brucella melitensis are the main pathogen of brucellosis epidemics in China, most of which are located in northern China. However, there is limited knowledge about the epidemiology of osteoarthritis-associated brucellosis. This study was aimed to reveal the prevalence of osteoarthritis-associated brucellosis in Inner Mongolia and also to investigate the molecular characteristics of B. melitensis isolates. METHODS AND RESULTS: In 2018, the osteoarthritis symptoms of brucellosis in the Brucellosis department of a hospital in Inner Mongolia were investigated. Twenty osteoarthritis-associated B. melitensis strains, isolated from the inpatients in Inner Mongolia during 2013-2017, were subjected to whole genome sequencing. The multilocus sequence type (MLST) and core genome SNP (cgSNP) analysis were conducted to detect molecular epidemiological characteristics. The incidence of brucellosis osteoarthritis symptoms in males (85/120, 70.8%) was significantly higher than that in females (35/120, 29.2%), and the age of patients was concentrated between 41 and 60 years old. In silico analyses indicated ST8 was the prevalent sequence type and the transmission of osteoarthritis-associated B. melitensis among different geographical areas. All strains carry virulence genes, including cgs, lpsA, manCoAg, pgm, pmm, virB4, wbdA and wboA. CONCLUSION: Our study showed the close epidemiologically connection of osteoarthritis-associated B. melitensis strains in northern China. And ST8 was the prevalent sequence type which need our attention.

Mitochondria targeted biomimetic platform for chemo/photodynamic combination therapy against osteosarcoma.

Clinical treatment for osteosarcoma (OS) is still lacking effective means, and no significant progress in OS treatment have been made in recent years. Single chemotherapy has serious side effects and can produce drug resistance easily, resulting poor therapeutic effect. As a modern and non-invasive treatment form, photodynamic therapy (PDT) is widely used to treat diverse cancers. Chemotherapy in combination with PDT is a particularly efficient antitumor method that could overcome the defects of monotherapies. Since mitochondria is a key subcellular organelle involved in cell apoptosis regulation, targeting tumor cells mitochondria for drug delivery has become an important entry point for anti-tumor therapy. Herein, we rationally designed a core-shell structured biomimetic nanoplatform, i.e., D@SLNP@OSM-IR780, to achieve tumor homologous targeting and mitochondria targeted drug release for chemotherapy combined with PDT against OS. Upon 808 nm laser irradiation, D@SLNP@OSM-IR780 exhibited excellent photo-cytotoxicity in vitro. The excellent targeting effect of D@SLNP@OSM-IR780 in tumor tissues produced a tumor inhibition rate of 98.9% in vivo. We further indicated that synergistic chemo-photodynamic effect induced by D@SLNP@OSM-IR780 could activate mitochondria-mediated apoptosis pathway, along with host immune response and potential photothermal effect. On the whole, D@SLNP@OSM-IR780 is revealed to be a promising platform for OS targeted combination therapeutics.

The influence of iron on bone metabolism disorders.

Iron is a necessary trace element in the human body, and it participates in many physiological processes. Disorders of iron metabolism can cause lesions in many tissues and organs, including bone. Recently, iron has gained attention as an independent factor influencing bone metabolism disorders, especially the involvement of iron overload in osteoporosis. The aim of this review was to summarize the findings from clinical and animal model research regarding the involvement of iron in bone metabolism disorders and to elucidate the mechanisms behind iron overload and osteoporosis. Lastly, we aimed to describe the association between bone loss and iron overload. We believe that a reduction in iron accumulation can be used as an alternative treatment to assist in the treatment of osteoporosis, to improve bone mass, and to improve the quality of life of patients.

Association Between the Serum Copper Levels and Environmental Tobacco Exposure on the Risk of Overweight and Obesity in Children: a Study Based on the National Health and Nutrition Examination Survey.

This study was to assess the individual effects of serum copper levels and environmental tobacco exposure and their joint effects on the risk of overweight and obesity among children and adolescents of 6 to 19 year olds. We analyzed cross-sectional data from 1849 children and adolescents participating in the National Health and Nutrition Examination Survey (NHANES) collected between 2011 and 2016. Environmental tobacco exposure was determined by cotinine levels. The serum copper level was divided into < median group and ≥ median groups according to the median of 109.81 µg/dL. The outcome was overweight/obese in children and adolescents. Weighted multinomial multivariate logistic regression models were used to assess the association of serum copper and cotinine levels, with the risk of overweight/obesity, and the joint effects on the risk of overweight and obesity among children and adolescents. The subgroup analyses based on age, gender, and household smoking status were conducted. Among 1849 children and adolescents, 332 children and adolescents had overweight BMI, and 450 children and adolescents had obese BMI. Higher serum copper levels were associated with the risk of obesity in children and adolescents (odds ratio (OR) 2.96, 95% confidence interval (CI) 1.39-6.31, P = 0.006). A positive association between increasing levels of cotinine levels and the risk of overweight (OR 1.83, 95% CI 1.16-2.87, P = 0.010) and obesity (OR 2.56, 95% CI 1.03-6.40, P = 0.044) in children and adolescents was observed. A remarkable association was found between higher serum copper in combination with higher cotinine levels and the risk of overweight (OR 3.23, 95% CI 1.19-8.83, P = 0.023) and obesity (OR 8.76, 95% CI 2.14-35.87, P = 0.003) in children and adolescents. The subgroup analyses revealed positive associations between high serum copper levels in combination with high cotinine levels and overweight and obesity in children and adolescents aged ≥ 12 years, of female sex, and without smoking family members. There may exist a joint effect of serum copper levels and environmental tobacco exposure on overweight/obesity among children and adolescents. These findings offer an insight that early weight control and reduction of tobacco exposure and the detection of serum copper levels may be important in reducing the risk of obesity in children.

LKB1 and CRMP1 cooperatively promote the repair of the sciatic nerve injury.

After peripheral nervous system injury, Schwann cells (SCs) can repair axons by providing a growth-promoting microenvironment. The aim of this study is to explore the effects and mechanisms of LKB1 and CRMP1 on the repair of sciatic nerve injury (SNI). The expressions of LKB1 and CRMP1 were changed in rats with SNI from 12 h to 4 weeks by hematoxylin-eosin staining, RT-PCR assay, immunohistochemical staining, and western blotting. Immunofluorescence results show that LKB1 and CRMP1 are co-localized in the regenerated axons of the sciatic nerve tissue of SNI rats. Co-immunoprecipitation indicates that LKB1 interacts with CRMP1. LKB1 interference suppresses the phosphorylation level of CRMP1. Overexpression of LKB1 and CRMP1 promotes the invasion and migration of SCs, and nerve cell protuberance extends. The structure of the myelin sheath in the sciatic nerve of the model group was found to be loose and disordered. Rats in the model group had higher pain thresholds and heat sensitivity response times than those in the control group. Nerve conduction velocity, the latency of action potential, and the peak value of compound muscle action potential in the SNI group were significantly lower than those in the control group, and the muscle atrophy was severe. Overexpression of LKB1 may significantly improve the above conditions. However, the function of LKB1 to improve SNI is abolished by the interference of CRMP1. In summary, the interaction between LKB1 and CRMP promotes the migration and differentiation of SCs and the extension of neurons, thereby improving the repair of nerve injury.

Short-term intensive fasting enhances the immune function of red blood cells in humans.

BACKGROUND: Fasting is known to influence the immune functions of leukocytes primarily by regulating their mobilization and redistribution between the bone marrow and the peripheral tissues or circulation, in particular via relocalization of leukocytes back in the bone marrow. However, how the immune system responds to the increased risk of invasion by infectious pathogens with fewer leukocytes in the peripheral blood during fasting intervention remains an open question. RESULTS: We used proteomic, biochemical and flow cytometric tools to evaluate the impact of short-term intensive fasting (STIF), known as beego, on red blood cells by profiling the cells from the STIF subjects before and after 6 days of fasting and 6 days of gradual refeeding. We found that STIF, by triggering the activation of the complement system via the complement receptor on the membrane of red blood cells, boosts fairly sustainable function of red blood cells in immune responses in close relation to various pathogens, including viruses, bacteria and parasites, particularly with the pronounced capacity to defend against SARS-CoV-2, without compromising their oxygen delivery capacity and viability. CONCLUSION: STIF fosters the immune function of red blood cells and therefore, it may be considered as a nonmedical intervention option for the stronger capacity of red blood cells to combat infectious diseases.

Geniposide suppressed OX-LDL-induced osteoblast apoptosis by regulating the NRF2/NF-κB signaling pathway.

BACKGROUND: Osteoporosis (OP), due to microarchitectural alterations, is associated with decreased bone mass, declined strength, and increased fracture risk. Increased osteoblast apoptosis contributes to the progression of OP. Natural compounds from herbs provide a rich resource for drug screening. Our previous investigation showed that geniposide (GEN), an effective compound from Eucommia ulmoides, could protect against the pathological development of OP induced by cholesterol accumulation. METHODS: The rat OP models were duplicated. Dual-energy X-ray absorptiometry, hematoxylin and eosin staining, and immunohistochemistry were used to evaluate bone changes. TUNEL/DAPI staining assays were used for cell apoptosis detection. Protein expression was determined by western blotting assays. RESULTS: A high-fat diet promoted OP development in vivo, and OX-LDL stimulated osteoblast apoptosis in vitro. GEN exhibited protective activities against OX-LDL-induced osteoblast apoptosis by increasing the NRF2 pathway and decreasing the NF-κB pathway. PDTC, an NF-κB inhibitor, could further promote the biological functions of GEN. In contrast, ML385, an NRF2 inhibitor, might eliminate GEN's protection. CONCLUSION: GEN suppressed OX-LDL-induced osteoblast apoptosis by regulating the NRF2/NF-κB signaling pathway.

Osteophilic and Dual-Regulated Alendronate-Gene Lipoplexes for Reversing Bone Loss.

The pathogenesis of postmenopausal osteoporosis (PMOP) is mainly determined by the adhesion of osteoclasts to the bone matrix and the involvement of various molecules in bone resorption. The dual regulation strategy of the physical barriers of bone matrix and intracellular gene regulation generated by advanced biomaterials is a decent alternative for the treatment of PMOP. Herein, for the first time, it is identified that hsa-miR-378i/mmu-miR-378a-3p are closely associated with PMOP. Then, an osteophilic and dual-regulated alendronate-gene lipoplex (antagomir@Aln-Lipo), composed of medicative alendronate-functionalized liposomal vehicle and encapsulated specific microRNAs is engineered, for bone-targeting delivery of genes to achieve combined mitigation of bone loss. Alendronate targets hydroxyapatite in the bone matrix and occupies the adhesion site of osteoclasts, thus providing the "physical barriers". Antagomir is coupled precisely to specific endogenous microRNAs, thus providing the "genetic signals". These functionalized lipoplexes exhibited long-term stability and good transfection efficiency. It is proven that antagomir@Aln-Lipo could synergistically regulate osteoclastogenesis and bone resorption in vitro and in vivo. Furthermore, intravenous injection of antagomir@Aln-Lipo efficiently reverses bone loss through a dual mechanism driven by alendronate and antagomir-378a-3p. In conclusion, the osteophilic and dual-regulated antagomir@Aln-Lipo offers a brand-new bifunctional strategy for the precise treatment of PMOP.

Avermectin reduces bone mineralization via the TGF-ß signaling pathway in zebrafish.

Avermectin, a widely used insecticide, is primarily effective against animal parasites and insects. Given its extensive application in agriculture, a large amount of avermectin accumulates in natural water bodies. Studies have shown that avermectin has significant toxic effects on various organisms and on the nervous system, spine, and several other organs in humans. However, the effects of avermectin on bone development have not been reported yet. In this study, zebrafish embryos were treated with different concentrations of avermectin to explore the effects of avermectin on early bone development. The results showed that avermectin disturbed early bone development in zebrafish, caused abnormal craniofacial chondrogenesis, and reduced bone mineralization. Avermectin treatment significantly reduced mineralization in zebrafish scales and increased osteoclast activity. Real-time quantitative PCR results showed that avermectin decreased the expression of genes related to osteogenesis and transforming growth factor-ß (TGF-ß) and bone morphogenetic protein (BMP) signaling pathways. The TGF-ß inhibitor SB431542 rescued avermectin-induced bone mineralization and osteogenesis related gene expression in zebrafish during early development. Thus, this study provides insight into the mechanism of damage caused by avermectin on bone development, thus helping demonstrate its toxicity.

Role of Iron Accumulation in Osteoporosis and the Underlying Mechanisms.

Osteoporosis is prevalent in postmenopausal women. The underlying reason is mainly estrogen deficiency, but recent studies have indicated that osteoporosis is also associated with iron accumulation after menopause. It has been confirmed that some methods of decreasing iron accumulation can improve the abnormal bone metabolism associated with postmenopausal osteoporosis. However, the mechanism of iron accumulation-induced osteoporosis is still unclear. Iron accumulation may inhibit the canonical Wnt/ß-catenin pathway via oxidative stress, leading to osteoporosis by decreasing bone formation and increasing bone resorption via the osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-B ligand (RANKL)/receptor activator of nuclear factor kappa-B (RANK) system. In addition to oxidative stress, iron accumulation also has been reported to inhibit either osteoblastogenesis or osteoblastic function as well as to stimulate either osteoclastogenesis or osteoclastic function directly. Furthermore, serum ferritin has been widely used for the prediction of bone status, and nontraumatic measurement of iron content by magnetic resonance imaging may be a promising early indicator of postmenopausal osteoporosis.

The Ubiquitination of RIPK2 is Mediated by Peli3 and Negatively Regulates the Onset of Infectious Osteomyelitis.

Osteomyelitis is the infection and destruction of the bone. To date, there is no universal protocol for its treatment. Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) has been implicated in osteomyelitis development. However, the detailed mechanism remains unknown. Here, 6-8w wild-type or Pellino E3 Ubiquitin Protein Ligase Family Member 3 (Peli3)-deficient mice were injected with Staphylococcus aureus to induce osteomyelitis. RAW264.7 cells or bone marrow-derived macrophages isolated from mice were treated with lipopolysaccharide (LPS). Knocking down Peli3 in RAW264.7 cells increased the expression of inflammatory cytokines (interleukin-1ß, interleukin-6, and tumor necrosis factor-α) after LPS stimulation. Inflammation was also activated in S. aureus-induced Peli3-deficient mice. Moreover, S. aureus-infected Peli3-deficient mice also displayed more severe symptoms of osteomyelitis than S. aureus-infected wild-type mice. Moreover, Peli3 targets and degrades RIPK2 through K48-linked ubiquitination, and negatively modulates osteomyelitis by degrading RIPK2. Our data further expands the current understanding of RIPK2 in osteomyelitis, and suggests that RIPK2 might serve as a novel therapeutic target for treating osteomyelitis.

Regulating Type H Vessel Formation and Bone Metabolism via Bone-Targeting Oral Micro/Nano-Hydrogel Microspheres to Prevent Bone Loss.

Postmenopausal osteoporosis is one of the most prevalent skeletal disorders in women and is featured by the imbalance between intraosseous vascularization and bone metabolism. In this study, a pH-responsive shell-core structured micro/nano-hydrogel microspheres loaded with polyhedral oligomeric silsesquioxane (POSS) using gas microfluidics and ionic cross-linking technology are developed. This micro/nano-hydrogel microsphere system (PDAP@Alg/Cs) can achieve oral delivery, intragastric protection, intestinal slow/controlled release, active targeting to bone tissue, and thus negatively affecting intraosseous angiogenesis and osteoclastogenesis. According to biodistribution data, PDAP@Alg/Cs can successfully enhance drug intestinal absorption and bioavailability through intestine adhesion and bone targeting after oral administration. In vitro and in vivo experiments reveal that PDAP@Alg/Cs promoted type H vessel formation and inhibited bone resorption, effectively mitigating bone loss by activating HIF-1α/VEGF signaling pathway and promoting heme oxygenase-1 (HO-1) expression. In conclusion, this novel oral micro/nano-hydrogel microsphere system can simultaneously accelerate intraosseous vascularization and decrease bone resorption, offering a brand-new approach to prevent postmenopausal osteoporosis.