Inhibition of fibroblast activation protein ameliorates cartilage matrix degradation and osteoarthritis progression.

Fibroblast activation protein (Fap) is a serine protease that degrades denatured type I collagen, α2-antiplasmin and FGF21. Fap is highly expressed in bone marrow stromal cells and functions as an osteogenic suppressor and can be inhibited by the bone growth factor Osteolectin (Oln). Fap is also expressed in synovial fibroblasts and positively correlated with the severity of rheumatoid arthritis (RA). However, whether Fap plays a critical role in osteoarthritis (OA) remains poorly understood. Here, we found that Fap is significantly elevated in osteoarthritic synovium, while the genetic deletion or pharmacological inhibition of Fap significantly ameliorated posttraumatic OA in mice. Mechanistically, we found that Fap degrades denatured type II collagen (Col II) and Mmp13-cleaved native Col II. Intra-articular injection of rFap significantly accelerated Col II degradation and OA progression. In contrast, Oln is expressed in the superficial layer of articular cartilage and is significantly downregulated in OA. Genetic deletion of Oln significantly exacerbated OA progression, which was partially rescued by Fap deletion or inhibition. Intra-articular injection of rOln significantly ameliorated OA progression. Taken together, these findings identify Fap as a critical pathogenic factor in OA that could be targeted by both synthetic and endogenous inhibitors to ameliorate articular cartilage degradation.

Exosome modification to better alleviates endoplasmic reticulum stress induced chondrocyte apoptosis and osteoarthritis.

Osteoarthritis (OA) is characterized by cartilage matrix degeneration and chondrocyte apoptosis. Prolonged endoplasmic reticulum (ER) stress participates in chondrocyte apoptosis and cartilage degeneration in OA progression. miR-486-5p could suppress the apoptosis of nucleus pulposus cells and cardiomyocyte, yet whether miR-486-5p modified exosomes could modulate ER stress and apoptosis of chondrocytes remain unknown. We validated the increased inflammation and ER stress in OA synovium and cartilage, and the inhibition of ER stress could attenuate the IL-1ß induced chondrocyte apoptosis. Administration of exogenous miR-486-5p could inhibit the ER stress, alleviate chondrocytes apoptosis and promote matrix regeneration. In comparison with direct administration of miR-486-5p and miR-486-5p overexpressing ADSCs, miR-486-5p modified exosomes indicated a better effect in modulating chondrocyte homeostasis. MiR-486-5p containing exosomes could also regulate macrophage polarization. Our IVIS imaging data validated that intraarticular injection of miR-486-5p containing exosomes could sustain for at least 7 days. MiR-486-5p containing exosomes showed a better effect on alleviating rats OA compared with direct administration of miR-486-5p and miR-486-5p overexpressing ADSCs. Our data demonstrated that miR-486-5p modified exosomes have a better effect on alleviating chondrocyte apoptosis and osteoarthritis. This study provides evidence of this efficient strategy of exosomal miRNA delivery and the miRNA-based therapy for OA.

Clinical effect of arthroscopic long head of biceps transfer and tenodesis on irreparable rotator cuff tear.

OBJECTIVE: To explore the clinical effect of arthroscopic long head of biceps transfer and tenodesis for on irreparable rotator cuff tear. METHODS: A total of 18 patients with irreparable rotator cuff tear who were treated in the Dongfang Hospital Affiliated to Tongji University School of Medicine from April 2018 to March 2020 were included in this study. They all underwent arthroscopic long head of biceps transfer and tenodesis. Shoulder joint motions (forward flexion, abduction, and external rotation angle) and magnetic resonance imaging (MRI) were performed. Moreover, visual analogue scale (VAS) and university of California Los Angeles (UCLA) score were conducted during follow-up. RESULTS: Preoperative symptoms lasted from 3 to 16 months, with an average duration of 10 months. All patients healed in the first stage without obvious complications were included. All patients were followed up for 4 to 14 months after the surgery, with an average duration of 11.1 months. The range of shoulder joint motions, including forward flexion (80.52° ± 31.19° vs. 149.47° ± 28.36°), abduction (65.13° ± 37.59° vs. 152.46° ± 28.64°) and lateral rotation (30.17° ± 15.15° vs. 71.49° ± 11.42°) was significantly improved after operation (P < 0.05). The VAS score was notably decreased after operation (8.46 ± 0.80 vs. 1.55 ± 0.70), but the UCLA score was markedly increased (15.27 ± 2.89 vs. 31.17 ± 2.36). MRI imaging showed that 15 patients had good tissue healing, with a healing rate of 83.3% (15/18). CONCLUSION: Arthroscopy of the biceps long head tendon transposition can significantly relieve pain in patients with large rotator cuff tears, improve joint mobility, and restore joint function.

Genistein loaded into microporous surface of nano tantalum/PEEK composite with antibacterial effect regulating cellular response in vitro, and promoting osseointegration in vivo.

Poly(ether-ether-ketone) (PEEK) with good biocompatibility exhibits high mechanical strengths but bioinert. In addition, tantalum (Ta) possesses outstanding osteogenesis but high density and elastic modulus, and cost. In this study, by blending Ta nanoparticles with PEEK, Ta/PEEK composite (TP) was prepared, which was then treated by concentrated sulfuric acid to form a microporous surface containing Ta particles on TP (TPS). Moreover, genistein (GS) with antibacterial property was loaded into the microporous surface of TPS (TPSG). Compared with TP, the surface properties (e.g., surface roughness and hydrophilicity) of TPS was obviously improved because of the microporous surface including Ta nanoparticles. Moreover, TPS showed low antibacterial properties because of presence of sulfonic group while TPSG exhibited excellent antibacterial properties due to GS loaded into the microporous surface. Furthermore, compared with TP, TPS obviously promoted attachment and proliferation of MG63 cells, while TPSG with GS remarkably inducing osteogenic differentiation of the cells compared with TPS in vitro. Moreover, in comparison with TP, TPS with optimized surface properties promoted new bone regeneration and osseointegration, while TPSG loading GS further enhanced bone regeneration as well as osseointegration in vivo. In summary, the GS loaded into microporous surface including Ta nanoparticles of TPSG exhibited antibacterial and osteogenic activity, which would have great potential for bone tissue repair.

In Vivo Studies of Mesenchymal Stem Cells in the Treatment of Meniscus Injury.

This review summarizes the literature of preclinical studies and clinical trials on the use of mesenchymal stem cells (MSCs) to treat meniscus injury and promote its repair and regeneration and provide guidance for future clinical research. Due to the special anatomical features of the meniscus, conservative or surgical treatment can hardly achieve complete physiological and histological repair. As a new method, stem cells promote meniscus regeneration in preclinical research and human preliminary research. We expect that, in the near future, in vivo injection of stem cells to promote meniscus repair can be used as a new treatment model in clinical treatment. The treatment of animal meniscus injury, and the clinical trial of human meniscus injury has begun preliminary exploration. As for the animal experiments, most models of meniscus injury are too simple, which can hardly simulate the complexity of actual meniscal tears, and since the follow-up often lasts for only 4-12 weeks, long-term results could not be observed. Lastly, animal models failed to simulate the actual stress environment faced by the meniscus, so it needs to be further studied if regenerated meniscus has similar anti-stress or anti-twist features. Despite these limitations, repair of the meniscus by MSCs has great potential in clinics. MSCs can differentiate into fibrous chondrocytes, which can possibly repair the meniscus and provide a new strategy for repairing meniscus injury.

Adipose-derived stem cell exosomes facilitate rotator cuff repair by mediating tendon-derived stem cells.

Aim: To evaluate the potential capability of adipose-derived stem cell exosomes (ADSC-exos) on rotator cuff repair by mediating the tendon-derived stem cells (TDSCs) and explored the mechanism. Methods: First, we investigated the growth, survival and migration of TDSCs in the presence of ADSC-exos in vitro. Using a rat rotator cuff injury model to analyze the ability of the ADSC-exos to promote rotator cuff healing in vivo. Results: The hydrogel with ADSC-exos significantly improved the osteogenic and adipogenesis differentiation and enhanced the expression of RUNX2, Sox-9, TNMD, TNC and Scx and the mechanical properties of the articular portion. Conclusion: The ADSC-exos have the potential to promote the rotator cuff repair by mediating the TDSCs.

Nanostructured Coating of Non-Crystalline Tantalum Pentoxide on Polyetheretherketone Enhances RBMS Cells/HGE Cells Adhesion.

PURPOSE: As a dental material, polyetheretherketone (PEEK) is bioinert that does not induce cellular response and bone/gingival tissues regeneration. This study was to develop bioactive coating on PEEK and investigate the effects of coating on cellular response. MATERIALS AND METHODS: Tantalum pentoxide (TP) coating was fabricated on PEEK surface by vacuum evaporation and responses of rat bone marrow mesenchymal stem (RBMS) cells/human gingival epithelial (HGE) were studied. RESULTS: A dense coating (around 400 nm in thickness) of TP was closely combined with PEEK (PKTP). Moreover, the coating was non-crystalline TP, which contained many small humps (around 10 nm in size), exhibiting a nanostructured surface. In addition, the roughness, hydrophilicity, surface energy, and protein adsorption of PKTP were remarkably higher than that of PEEK. Furthermore, the responses (adhesion, proliferation, and osteogenic gene expression) of RBMS cells, and responses (adhesion and proliferation) of HGE cells to PKTP were remarkably improved in comparison with PEEK. It could be suggested that the nanostructured coating of TP on PEEK played crucial roles in inducing the responses of RBMS/HGE cells. CONCLUSION: PKTP with elevated surface performances and outstanding cytocompatibility might have enormous potential for dental implant application.

A comparative assessment of adipose-derived stem cells from subcutaneous and visceral fat as a potential cell source for knee osteoarthritis treatment.

The intra-articular injection of adipose-derived stem cells (ASCs) is a novel potential therapy for patients with osteoarthritis (OA). However, the efficacy of ASCs from different regions of the body remains unknown. This study investigated whether ASCs from subcutaneous or visceral adipose tissue provide the same improvement of OA. Mouse and human subcutaneous and visceral adipose tissue were excised for ASC isolation. Morphology, proliferation, surface markers and adipocyte differentiation of subcutaneous ASCs (S-ASCs) and visceral ASCs (V-ASCs) were analysed. A surgically induced rat model of OA was established, and 4 weeks after the operation, S-ASCs, V-ASCs or phosphate-buffered saline (PBS, control) were injected into the articular cavity. Histology, immunohistochemistry and gene expression analyses were performed 6 weeks after ASC injection. The ability of ASCs to differentiate into chondrocytes was assessed by in vitro chondrogenesis, and the immunosuppressive activity of ASCs was evaluated by co-culturing with macrophages. The proliferation of V-ASCs was significantly greater than that of S-ASCs, but S-ASCs had the greater adipogenic capacity than V-ASCs. In addition, the infracted cartilage treated with S-ASCs showed significantly greater improvement than cartilage treated with PBS or V-ASCs. Moreover, S-ASCs showed better chondrogenic potential and immunosuppression in vitro. Subcutaneous adipose tissue is an effective cell source for cell therapy of OA as it promotes stem cell differentiation into chondrocytes and inhibits immunological reactions.