Journal of Orthopaedic Translation最新文献

Background

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a common bone and joint disease. There is currently a lack of effective treatment for GIONFH, and the disease progression may lead to total hip arthroplasty (THA). The exact mechanism of GIONFH pathogenesis remains unsettled, and emerging evidence indicates that the overactivation of osteoclasts plays a pivotal role in the occurrence and progression of this condition. Our previous study has shown that cycloastragenol (CAG), a triterpenoid saponin with multiple bioactivities, is a natural osteoclast inhibitor and has a protective effect on bone loss. However, its effect on GIONFH remains unclear.

Methods

In this study, methylprednisolone (MPS) (20 mg/kg) was administered via gluteal muscle injection to female Sprague–Dawley (SD) rats to induce GIONFH, and different doses of CAG (5 and 15 mg/kg) were dispensed intraperitoneally for intervention. Micro-CT screening and angiography were applied to determine the shaping of necrotic lesions, the loss of trabecular bone, and the change in the local blood supply. The molecular mechanism was established by Real-time qPCR and Western blotting. Hematoxylin and eosin (H&E) staining was performed to identify empty lacunae in the femoral head.

Results

CAG treatment shanked the necrotic lesion area, inhibited the trabecular bone loss, and improved the local blood supply in the femoral head. In addition, CAG medication lowered the ratio of Tnfsf11 (encoding RANKL) to Tnfrsf11b (encoding OPG) and the expression of osteoclast-specific genes, including Acp5 and Ctsk. Consistently, CAG treatment exhibited a dose-dependent weakening effect on the expression of osteoclastogenesis and bone resorption-related proteins, including TRAP, CTSK, and MMP9. CAG addition also alleviated the occurrence of empty lacunae in the subchondral region.

Conclusion

Our discoveries demonstrate that CAG is a potential option for hip preservation therapy in GIONFH patients.

Translational potential of this article

The protective effect of CAG on rats with GIONFH can be translated into clinical use.

Objectives

To investigate the potential role of Ribosomal protein L35 (RPL35) in regulating chondrocyte catabolic metabolism and to examine whether osteoarthritis (OA) progression can be delayed by overexpressing RPL35 in a mouse compression loading model.

Methods

RNA sequencing analysis was performed on chondrocytes treated with or without 20 % elongation strain loading for 24 h. Experimental OA in mice was induced by destabilization of the medial meniscus and compression loading. Mice were randomly assigned to a sham group, an intra-articular adenovirus-mediated overexpression of the negative group, and an intra-articular adenovirus-mediated overexpression of the RPL35 operated group. The Osteoarthritis Research Society International score was used to evaluate cartilage degeneration. Immunostaining and western blot analyses were conducted to detect relative protein levels. Primary mouse chondrocytes were treated with 20 % elongation strain loading for 24 h to investigate the role of RPL35 in modulating chondrocyte catabolic metabolism and regulating cellular senescence in chondrocytes.

Results

The protein expression of RPL35 in mouse chondrocytes was significantly reduced when excessive mechanical loading was applied, while elevated protein levels of RPL35 protected articular chondrocytes from degeneration. In addition, the RPL35 knockdown alone induced chondrocyte senescence, decreased the expression of anabolic markers, and increased the expression of catabolic markers in vitro in part through the hedgehog (Hh) pathway.

Conclusions

These findings demonstrated a functional pathway important for OA development and identified intra-articular injection of RPL35 as a potential therapy for OA prevention and treatment.

The translational potential of this article

It is necessary to develop new targeted drugs for OA due to the limitations of conventional pharmacotherapy. Our study explores and demonstrates the protective effect of RPL35 against excessive mechanical stress in OA models in vivo and in vitro in animals. These findings might provide novel insights into OA pathogenesis and show its translational potential for OA therapy.

Minimally invasive surgery for hallux valgus correction, has been attracting great interests in the recent decades, due to the potential benefits of less pain, decreased recovery times, smaller scars with better cosmesis, and improved early post-operative range of motion. The most recent developments in minimally invasive surgery have evolved into the third generation with modifications of the chevron-type osteotomy. This evidence-based clinical guideline of the third generation minimally invasive surgery for hallux valgus is initiated and developed collectively by the Foot and Ankle Committee of Orthopedic Branch of Chinese Medical Doctor Association, Foot and Ankle Committee of Sports Medicine Branch of Chinese Medical Doctor Association, and Foot and Ankle Expert Committee of Orthopedic Branch of the Chinese Association of the Integrative Medicine. This clinical guideline provides recommendations for indications, contraindications, operative planning and techniques, post-operative management, management of complications, and prognosis of the third generation minimally invasive surgery for hallux valgus.

The Translational Potential of this Article This comprehensive guideline aims to establish standardized recommendations for the indications, contraindications, operative techniques, and post-operative management of the third generation minimally invasive surgery for hallux valgus. By adhering to this guideline, the success rate of the procedure could be maximized. This comprehensive guideline serves as a valuable reference for practitioners interested in or preparing to perform minimally invasive surgery for hallux valgus.

Objective

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage damage. In order to find a safer and more effective drug to treat OA, we investigated the role of quercetin-3-O-β-D-glucuronide (Q3GA) in OA.

Methods

We used qRT-PCR and western blots to detect the effects of Q3GA on extracellular matrix (ECM) and inflammation related genes and proteins in interleukin-1β (IL-1β) induced chondrocytes. We determined the effect of Q3GA on the NF-κB pathway using western blots and immunofluorescence. Moreover, the effect of Q3GA on the Nrf2 pathway was evaluated through molecular docking, western blots, and immunofluorescence experiments and further validated by transfection with Nrf2 siRNA. Subsequently, we established a rat model of OA and injected Q3GA into the joint cavity for treatment. After 5 weeks of Q3GA administration, samples were obtained for micro-computed tomography scanning and histopathological staining to determine the effects of Q3GA on OA rats.

Results

We found that Q3GA reduced the degradation of ECM and the expression of inflammatory related proteins and genes in primary chondrocytes of rats induced by IL-1β, as well as the expression of nitric oxide (NO) and reactive oxygen species (ROS). It inhibited the activation of the NF-κB pathway by increasing the expression of Nrf2 in the nucleus. In addition, Q3GA inhibited cartilage degradation in OA rats and promoted cartilage repair.

Conclusion

Q3GA attenuates OA by inhibiting ECM degradation and inflammation via the Nrf2/NF-κB axis.

The translational potential of this article

The results of our study demonstrate the promising potential of Q3GA as a candidate drug for the treatment of OA and reveal its key mechanisms.

Background

Reliable animal models are critical for preclinical research and should closely mimic the disease. With respect to route of infection, pathogenic agent, disease progression, clinical signs, and histopathological changes. Sheep have similar bone micro- and macrostructure as well as comparable biomechanical characteristics to humans. Their use in bone research is established, however their use in bone infection research is limited. This systematic review will summarise the key features of the available bone infection models using sheep, providing a reference for further development, validation, and application.

Method

This systematic review was designed according to the PRISMA guidelines and registered with PROSPERO. Quality was assessed using SYRICLE's risk of bias tool adapted for animal studies. PubMed, MEDLINE, Web of Science and EMBASE were searched until March 2022.1921 articles were screened by two independent reviewers, and 25 were included for analysis.

Results

Models have been developed in nine different breeds. Staphylococcus aureus was used in the majority of models, typically inoculating 10⁸ colony forming units in tibial or femoral cortical defects. Infection was established with either planktonic or biofilm adherent bacteria, with or without foreign material implanted. Most studies used both radiological and microbiological analyses to confirm osteomyelitis.

Conclusions

There is convincing evidence supporting the use of sheep in bone infection models of clinical disease. The majority of sheep studied demonstrated convincing osteomyelitis and tolerated the infection with minimal complications. Furthermore, the advantages of comparable biology and biomechanics may increase the success for translating in vivo results to successful therapies.

The Translational potential of this article

In the realm of preclinical research, the translation to viable clinical therapies is often perilous, and the quest for reliable and representative animal models remains paramount. This systematic review accentuates the largely untapped potential of sheep as large animal models, especially in bone infection research. The anatomical and biomechanical parallels between sheep and human bone structures position sheep as an invaluable asset for studying osteomyelitis and periprosthetic joint infection. This comprehensive exploration of the literature demonstrates the robustness and translational promise of these models. Furthermore, this article underscores the potential applicability for sheep in developing effective therapeutic strategies for human bone infections.

Research background

The role of osteocytes in maintaining bone mass has been progressively emphasized. Pip5k1c is the most critical isoform among PIP5KIs, which can regulate cytoskeleton, biomembrane, and Ca²⁺ release of cells and participate in many processes, such as cell adhesion, differentiation, and apoptosis. However, its expression and function in osteocytes are still unclear.

Materials and methods

To determine the function of Pip5k1c in osteocytes, the expression of Pip5k1c in osteocytes was deleted by breeding the 10-kb mouse Dmp1-Cre transgenic mice with the Pip5k1c^fl/fl mice. Bone histomorphometry, micro-computerized tomography analysis, immunofluorescence staining and western blotting were used to determine the effects of Pip5k1c loss on bone mass. In vitro, we explored the mechanism by siRNA knockdown of Pip5k1c in MLO-Y4 cells.

Results

Pip5k1c expression was decreased in osteocytes in senescent and osteoporotic tissues both in humans and mice. Loss of Pip5k1c in osteocytes led to a low bone mass in long bones and spines and impaired biomechanical properties in femur, without changes in calvariae. The loss of Pip5k1c resulted in the reduction of the protein level of type 1 collagen in tibiae and MLO-Y4 cells. Osteocyte Pip5k1c loss reduced the osteoblast and bone formation rate with high expression of sclerostin, impacting the osteoclast activities at the same time. Moreover, Pip5k1c loss in osteocytes reduced expression of focal adhesion proteins and promoted apoptosis.

Conclusion

Our studies demonstrate the critical role and mechanism of Pip5k1c in osteocytes in regulating bone remodeling.

The translational potential of this article

Osteocyte has been considered to a key role in regulating bone homeostasis. The present study has demonstrated that the significance of Pip5k1c in bone homeostasis by regulating the expression of collagen, sclerostin and focal adhesion expression, which provided a possible therapeutic target against human metabolic bone disease.

Background

Diabetic foot is a major complication of diabetes. The bone transverse transport method could be applied in clinics for treatment, which could improve the metabolism of the tissues via lasting distraction forces. However, the process’ specific regulating mechanism is still unknown.

Methods

Based on the notion that the healing of bones involves the recruitment of calcium ions, in this study, we established the model of tibial cortex transverse transport (TTT) on rats and then used tissue immunologic detection, such as the double fluorescent staining to explore the expression of the calcium channels’ calcium release-activated calcium modulator 1 (Orai1)/stromal interaction molecule 1 (STIM1), which belong to the store-operated calcium entry (SOCE) signaling pathways on the tissues around the bone transport area. By using the laser capture microdissection (LCM) tool, we acquired samples of tissues around the bone and endeavored to identify pivotal protein molecules. Subsequently, we validated the functions of key protein molecules through in vitro and in vivo experiments.

Results

After protein profile analysis, we found the differentially expressed key protein osteopontin (OPN). The in vitro experiments verified that, being stimulated by OPN, the migration, proliferation, and angiogenesis of human umbilical vein endothelial cells (HUVEC) were observed to be enhanced. The activation of Orai1/STIM1 might increase the activity of endothelial nitric oxide synthase (eNOS) and its effect on releasing nitric oxide (NO). Subsequently, the migration and proliferation of the HUVECs are improved, which ultimately accelerates wound healing. These signaling pathway was also observed in the OPN-stimulated healing process of the skin wound surface of diabetic mice.

Conclusion

This study identifies the molecular biological mechanism of OPN-benefited the migration and proliferation of the HUVECs and provides ideas for searching for new therapeutic targets for drugs that repair diabetes-induced wounds to replace invasive treatment methods.

The translational potential of this article

The OPN is highly expressed in the tissues surrounding the TTT bone transfer area, which may possibly stimulate the activation of eNOS to increase NO release through the SOCE pathway mediated by Orai1/STIM1. This mechanism may play a significant role in the angiogenesis of diabetic foot's wounds promoted by TTT, providing new therapeutic strategies for the non-surgical treatment for this disease.

Background

From 1990 to 2019, low back pain (LBP) was the leading cause of years lived with disability (YLDs) in China. However, the change patterns of LBP and its risk factors in China remain unclear.

Methods

Data from the Global Burden of Disease Study 2019 were used. We used the join-point regression model and age-period-cohort analysis to evaluate the time trends of attributable risk factors on the burden of LBP.

Results

In 2019, the risk factors included in this analysis accounted for 4.36 million YLDs of LBP, representing 42.2% of all YLDs of LBP in China, with 2.86 million due to occupational ergonomic factors, 1.74 million due to smoking, and 0.46 million due to high body mass index (BMI). The age-standardized YLD rates of LBP showed downward trends during 1990–2019, while there was a faster decline between 1990 and 1994. The curves of local drifts, which reflected the average annual percentage change across age groups, showed an increasing trend with age for high BMI and smoking, and a downward trend for occupational ergonomic factors. The YLD rates for LBP increased dramatically with age for high BMI, while it reached a peak at 40–60 years old for occupational ergonomic factors, and 65–80 years old for smoking. The period and cohort rate ratios of LBP YLD decreased in the past 3 decades for occupational ergonomic factors and smoking, while increased for high BMI.

Conclusions

Our results provided strong evidence that there were diverse changing patterns for different risk factors, highlighting the need for risk-specific strategies.

The translational potential of this article

China has the largest senior population and the fastest aging population in the world. Given that LBP typically occurs in the senior population, there would be an increasing LBP burden on China's health system. This suggests that effective strategies for LBP prevention should be strictly implemented in China, particularly in the senior population, which is of crucial translational potential.

Background

Alveolar bone destruction due to periodontal disease often requires a bone graft substitute to reconstruct the anatomical structures and biological functions of the bone tissue. Despite significant advances in the development of foreign ion-doped nonstoichiometric wollastonite bioceramics (CaSiO₃, nCSi) for alveolar bone regeneration over the past decade, the in vivo biosafety and osteogenesis of nCSi scaffolds remain uncertain. In this study, we developed a customized porous nCSi scaffold to investigate the in vivo biocompatibility and osteogenic properties of nCSi bioceramics.

Methods

Six percent Mg-doped nCSi bioceramic scaffolds were fabricated by digital light processing (DLP), and the scaffold morphology, pore architecture, compressive strength, in vitro biodegradation, and apatite-forming ability of the bioceramic scaffolds were investigated systematically. Subsequently, an alveolar bone defect rabbit model was used to evaluate the biocompatibility and osteogenic efficacy of the nCSi bioceramics. Animal weight, hematological test, blood biochemical test, wet weight of the main organs, and pathological examination of the main organs were conducted. Micro-CT and histological staining were performed to analyze the osteogenic potential of the personalized bioceramic scaffolds.

Results

The nCSi scaffolds exhibited appreciable initial compressive strength (>30 MPa) and mild mechanical decay over time during in vitro biodissolution. In addition, the scaffolds induced apatite remineralization in SBF. Bioceramic scaffolds have been proven to have good biocompatibility in vivo after implantation into the alveolar bone defect of rabbits. No significant effects on the hematological indices, blood biochemical parameters, organ wet weight, or organ histopathology were detected from 3 to 180 days postoperatively. The porous scaffolds exhibited strong bone regeneration capability in the alveolar bone defect model of rabbits. Micro-CT and histological examination showed effective maintenance of bone morphology in the bioceramic scaffold group; however, depressed bone tissue was observed in the control group.

Conclusions

Our results suggest that personalized nCSi bioceramic scaffolds can be fabricated using the DLP technique. These newly developed strong bioceramic scaffolds exhibit good biocompatibility and osteogenic capability in vivo and have excellent potential as next-generation oral implants.

The translational potential of this article

Tissue-engineered strategies for alveolar bone repair require a bone graft substitute with appreciable biocompatibility and osteogenic capability. This article provides a systematic investigation of the in vivo biosafety and osteogenic property of nCSi to further development of a silicate-based bioceramics materials for clinical applications.

Skeletal muscle diseases, a broad category encompassing a myriad of afflictions such as acute muscle injury and muscular dystrophies, pose a significant health burden globally. These conditions often lead to muscle weakness, compromised mobility, and a diminished quality of life. In light of this, innovative and effective therapeutic strategies are fervently sought after. Exosomes, naturally extracellular vesicles with a diameter of 30–150 nm, pervade biological fluids. These microscopic entities harbor a host of biological molecules, including proteins, nucleic acids, and lipids, bearing a significant resemblance to their parent cells. The roles they play in the biological theater are manifold, influencing crucial physiological and pathological processes within the organism. In the context of skeletal muscle diseases, their potential extends beyond these roles, as they present a promising therapeutic target and a vehicle for targeted drug delivery. This potentially paves the way for significant clinical applications. This review aims to elucidate the mechanisms underpinning exosome action, their myriad biological functions, and the strides made in exosome research and application. A comprehensive exploration of the part played by exosomes in skeletal muscle repair and regeneration is undertaken. In addition, we delve into the use of exosomes in the therapeutic landscape of skeletal muscle diseases, providing a valuable reference for a deeper understanding of exosome applications in this realm. The concluding section encapsulates the prospective avenues for exosome research and the promising future they hold, underscoring the tremendous potential these diminutive vesicles possess in the field of skeletal muscle diseases.

The Translational Potential of this Article.

The comprehensive exploration of exosome's diverse biological functions and translational potential in the context of skeletal muscle diseases presented in this review underscores their promising future as a therapeutic target with significant clinical applications, thus paving the way for innovative and effective therapeutic strategies in this realm.