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The objective of the present study was to perform an in vivo assessment of a novel silk-collagen scaffold for anterior cruciate ligament (ACL) reconstruction. First, a silk-collagen scaffold was fabricated by combining sericin-extracted knitted silk fibroin mesh and type I collagen to mimic the components of the ligament. Scaffolds were electron-beam sterilized and rolled up to replace the ACL in 20 rabbits in the scaffold group, and autologous semitendinosus tendons were used to reconstruct the ACL in the autograft control group. At 4 and 16 weeks after surgery, grafts were retrieved and analyzed for neoligament regeneration and tendon-bone healing. To evaluate neoligament regeneration, H&E and immunohistochemical staining was performed, and to assess tendon-bone healing, micro-CT, biomechanical test, H&E and Russell-Movat pentachrome staining were performed. Cell infiltration increased over time in the scaffold group, and abundant fibroblast-like cells were found in the core of the scaffold graft at 16 weeks postoperatively. Tenascin-C was strongly positive in newly regenerated tissue at 4 and 16 weeks postoperatively in the scaffold group, similar to observations in the autograft group. Compared with the autograft group, tendon-bone healing was better in the scaffold group with trabecular bone growth into the scaffold. The results indicate that the silk-collagen scaffold has considerable potential for clinical application.

Background Sex hormone-binding globulin (SHBG) has been reported to be a risk factor associated with the development of arthritis by previous observational studies more so of three common forms of arthritis: osteoarthritis (OA), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). This study aimed to determine whether the concentrations of circulating SHBG are causally associated with the risk of OA, RA, and AS. Methods The two-sample Mendelian randomization (MR) approach was used for this study. The inverse-variance-weighted (IVW) method was used for the main analysis. Single-nucleotide polymorphisms (SNPs) associated with SHBG were selected from a large genome-wide association study (GWAS) of 28,837 European individuals. The summary statistics for OA, RA, and AS were extracted from the UK Biobank Resource ( n  = 361,141) and a GWAS dataset ( n  = 455,221). Results Positive causal associations were found between circulating SHBG concentrations and OA (effect = 1.086; 95% CI, 1.009 to 1.168; P  = 0.027) and RA (effect = 1.003; 95% CI, 1.000 to 1.007; P  = 0.047) in overall analyses. However, there was no evidence of association between SHBG levels and AS. Based on the stratification of skeletal sites, SHBG levels were found to be significantly associated with hip OA (effect = 1.423; 95% CI, 1.219 to 1.660; P  = 7.753 × 10 −6 ). However, this was not the case with knee OA. Conclusions There were positive causal effects of circulating SHBG on the development of OA and RA. Moreover, there was a site-specific association between SHBG and hip OA. Evidently, measurement of SHBG in serum could be valuable in the clinical assessment of arthritis especially in early screening and prevention of OA and RA. However, the mechanisms by which SHBG plays causal roles in the development of arthritis require further investigations.

Background Shoulder is vulnerable to dislocation owing to its anatomical structure and the increasing popularity of contact sports in young population. The management of first-time anterior shoulder dislocation in this group is still controversial and the prognosis are varied. This review aimed to compare the results of arthroscopic Bankart repair and conservative management for first-time traumatic anterior shoulder dislocation in young active patients. Methods Databases were searched till November 2021, and comparative studies between arthroscopic Bankart repair and conservative management for first-time traumatic anterior shoulder dislocation in young population were selected. Methodological quality of the studies was assessed according to the Cochrane Back Review Group 12-item scale. Outcome measures included recurrence of instability, return to play, subsequent instability surgery, and shoulder functional scores. Results The search returned 12 eligible trials with 786 participants. All the trials were of prospective design. After arthroscopic Bankart repair, patients experienced significantly less re-dislocation (7.5% vs. 53.0%, p  < 0.00001, I 2  = 0%), subluxation (3.1% vs. 24.2%, p  < 0.0001, I 2  = 0%), positive apprehension test (7.3% vs. 25.8%, p  = 0.002, I 2  = 11%), and subsequent surgical treatment for instability (5.6% vs. 37.8%, p  < 0.00001, I 2  = 0%) when compared with those underwent conservative management. And more patients returned to play (83.5% vs. 66.0%, p  = 0.03, I 2  = 81%) after arthroscopic Bankart repair. Outcomes regarding the functional scores did not reach a significant difference between the two cohorts. Conclusions Arthroscopic Bankart repair showed superiority over conservative management in terms of recurrence, return to play, and subsequent instability surgery during the follow-up in young active patients that encountered first episode of dislocation. As long-term prognosis is comparable, an immediate surgical stabilization might not be suitable for everyone.

Abstract Purpose Accumulating evidence implicates parathyroid hormone (PTH) in the development of osteoporosis. However, the causal effect of PTH on bone mineral density (BMD) remains unclear. Thus, this study is aimed at exploring the association between the concentrations of serum PTH and BMD. Methods The instrumental variables for PTH were selected from a large-scale genome-wide association study (GWAS; n = 29 155). Outcomes included BMD of the forearm (FA; n = 8143), femoral neck (FN; n = 33 297), lumbar spine (LS; n = 32 735), heel (HL; n = 394 929), and risk of fractures in these bones (n = 361 194). Furthermore, the BMD of 5 different age groups: 15 years or younger (n = 11 807), 15–30 (n = 4180), 30–45 (n = 10 062), 45–60 (n = 18 805), and 60 years or older (n = 22 504) were extracted from a GWAS meta-analysis study. The analyses were performed using the 2-sample Mendelian randomization method. Results Mendelian randomization analysis revealed that the level of serum PTH was inversely associated with BMD of FA (95% CI: -0.763 to -0.016), FN (95% CI: -0.669 to -0.304), and LS (95% CI: -0.667 to -0.243). A causal relationship between serum PTH levels and BMD was observed in individuals aged 30–45 (95% CI: -0.888 to -0.166), 45–60 (95% CI: -0.758 to -0.232), and over 60 years (95% CI: -0.649 to -0.163). Main Conclusions This study demonstrated that the concentrations of serum PTH is inversely associated with BMD of several bones. Further analysis revealed site- and age-specific correlations between serum PTH levels and BMD, which implies that the levels of serum PTH contribute to the development of osteoporosis.

Background COX-2, an inducible enzyme, is associated with inflammatory diseases and carcinogenesis. Overexpression of COX-2 occurs in many human malignancies, including osteosarcoma. COX-2 positivity is form 67 to 92% in osteosarcoma, and COX-2 expresses 141-fold more in cancer stem cell spheres than daughter adherent cells. In our study, we have reported that celecoxib, a cyclooxygenase-2 inhibitor, induces apoptosis in human osteosarcoma cell line MG-63 via down-regulation of PI3K/Akt. It has been confirmed that celecoxib enhances apoptosis and cytotoxic effect of cisplatin, although the mechanism remains unclear. Methods We have attempted to identify the anti-proliferation of celecoxib, a selective COX-2 inhibitor, and the combination of celecoxib and cisplatin in MG-63 cells, and to explore the potential molecular mechanisms involved. MG-63 cells were treated with the combination of celecoxib and cisplatin or either agent alone for 48 h in serum-supplemented medium. Results MDR1, MRP1, BCRP and Trkb, E-cadherin, β-catenin were significantly downregulated in cells treated with the combination of celecoxib and cisplatin, and decreased β-catenin level was found in cells with wortmannin, a specific PI3K inhibitor. Conclusion Therefore, celecoxib enhances anticancer effect of cisplatin and induces anoikis in osteosarcoma, which may be PI3K/Akt-dependent, and MDR and β-catenin-related. PI3K may be at the center of the celecoxib effects, which play an essential role in the regulation of MDR and anoikis.

Background Steroids are a leading cause of femoral head osteonecrosis. Currently there are no medications available to prevent and/or treat steroid-associated osteonecrosis. Low-intensity pulsed ultrasound (LIPUS) was approved by the FDA for treating delayed union of bone fractures. Some studies have reported that LIPUS can enhance bone formation and local blood flow in an animal model of fracture healing. However, whether the effect of osteogenesis and neovascularization by LIPUS can enhance the repair progress in steroid-associated osteonecrosis is unknown. Questions/purposes We hypothesized that LIPUS may facilitate osteogenesis and neovascularization in the reparative processes of steroid-associated osteonecrosis. Using a rabbit animal model, we asked whether LIPUS affects (1) bone strength and trabecular architecture; (2) blood vessel number and diameter; and (3) BMP-2 and VEGF expression. Methods Bilateral femoral head necrosis was induced by lipopolysaccharide and methylprednisolone in 24 rabbits. The left femoral heads of rabbits received LIPUS therapy (200 mW/cm 2 ) for 20 minutes daily and were classified as the LIPUS group. The right femoral heads of the same rabbits did not receive therapy and were classified as the control group. All rabbits were euthanized 12 weeks after LIPUS therapy. Micro-CT, biomechanical testing, histologic evaluation, immunohistochemistry, quantitative real-time PCR, and Western blot were used for examination of the effects of LIPUS. Results Twelve weeks after LIPUS treatment, the loading strength in the control group was 355 ± 38 N (95% CI, 315–394 N), which was lower (p = 0.028) than that in the LIPUS group (441 ± 78 N; 95% CI, 359–524 N). The bone tissue volume density (bone volume/total volume) in the LIPUS group (49.29% ± 12.37%; 95 % CI, 36.31%–62.27%) was higher (p = 0.022) than that in the control group (37.93% ± 8.37%; 95 % CI, 29.15%–46.72%). The percentage of empty osteocyte lacunae in the LIPUS group (17% ± 4%; 95% CI, 15%–20%) was lower (p = 0.002) than that in the control group (26% ± 9%; 95% CI, 21%–32%). The mineral apposition rate (μm/day) in the LIPUS group (2.3 ± 0.8 μm/day; 95% CI, 1.8 2.8 μm/day) was higher (p = 0.001) than that in the control group (1.6 ± 0.3 μm/day; 95% CL, 1.4–1.8 μm/day). The number of blood vessels in the LIPUS group (7.8 ± 3.6/mm 2 ; 95% CI, 5.5–10.1 mm 2 ) was greater (p = 0.025) than the number in the control group (5.7 ± 2.6/mm 2 ; 95% CI, 4.0–7.3 mm 2 ). Messenger RNA (mRNA) and protein expression of BMP-2 in the LIPUS group (75 ± 7, 95% CI, 70–79; and 30 ± 3, 95% CI, 28–31) were higher (both p < 0.001) than those in the control groups (46 ± 5, 95% CI, 43–49; and 15 ± 2, 95% CI, 14–16). However, there were no differences (p = 0.114 and 0.124) in mRNA and protein expression of vascular endothelial growth factor between the control (26 ± 3, 95% CI, 24–28; and 22 ± 6, 95% CI, 18–26) and LIPUS groups (28 ± 2, 95% CI, 26–29; and 23 ± 6, 95% CI, 19–27). Conclusions The results of this study indicate that LIPUS promotes osteogenesis and neovascularization, thus promoting bone repair in this steroid-associated osteonecrosis model. Clinical Relevance LIPUS may be a promising modality for the treatment of early-stage steroid-associated osteonecrosis. Further research, including clinical trials to determine whether LIPUS has a therapeutic effect on patients with early-onset steroid-associated osteonecrosis may be warranted.

NR4A3 is a member of nuclear receptor subfamily 4, which is an important regulator of cellular function and inflammation. In this study, high expression of NR4A3 in human osteoarthritis (OA) cartilage was firstly observed. To explore the relationship between NR4A3 and OA, we used a lentivirus overexpression system to simulate its high expression and study its role in OA. Additionally, siRNA‐mediated knockdown of NR4A3 was used to confirm the findings of overexpression experiments. The results showed the stimulatory effect of IL‐1β on cartilage matrix‐degrading enzyme expression such as MMP‐3, 9, INOS and COX‐2 was enhanced in NR4A3‐overexpressed chondrocytes and decreased in NR4A3‐knockdown chondrocytes at both mRNA and protein levels, while IL‐1β‐induced chondrocyte‐specific gene (collagen 2 and SOX‐9) degradation was only regulated by NR4A3 at protein level. Furthermore, overexpression of NR4A3 would also enhance EBSS‐induced chondrocytes apoptosis, while knockdown of NR4A3 decreased apoptotic level after EBSS treatment. A pathway study indicated that IL‐1β‐induced NF‐κB activation was enhanced by NR4A3 overexpression and reduced by NR4A3 knockdown. We suggest that NR4A3 plays a pro‐inflammatory role in the development of OA, and we also speculate that NR4A3 mainly regulates cartilage matrix‐degrading gene expression under inflammatory conditions via the NF‐κB pathway.

Long-term chronic inflammation after Achilles tendon injury is critical for tendinopathy. Platelet-rich plasma (PRP) injection, which is a common method for treating tendinopathy, has positive effects on tendon repair. In addition, tendon-derived stem cells (TDSCs), which are stem cells located in tendons, play a major role in maintaining tissue homeostasis and postinjury repair. In this study, injectable gelatine methacryloyl (GelMA) microparticles containing PRP laden with TDSCs (PRP–TDSC–GM) were prepared by a projection-based 3D bioprinting technique. Our results showed that PRP–TDSC–GM could promote tendon differentiation in TDSCs and reduce the inflammatory response by downregulating the PI3K–AKT pathway, thus promoting the structural and functional repair of tendons in vivo. Graphical Abstract

Previous observational studies have identified various risk factors associated with the development of osteoporosis, including sex hormone-binding globulin (SHBG). The aim of this study was to determine the potential causal effects of circulating SHBG concentrations on bone mineral density (BMD). Two-sample Mendelian randomization (MR) approach was applied in analyses. From summary-level data of genome-wide association studies (GWAS), we selected 11 single-nucleotide polymorphisms (SNPs) associated with SHBG levels as instrumental variable, and used summary statistics for BMD at forearm (FA) (n = 8143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498) and heel (HL) (n = 394,929), and total-body BMD of different age-stages (15 or less, 15–30, 30–45, 45–60, 60 or more years old) (n = 67,358). Inverse causal associations was observed between SHBG levels and FA BMD (Effect = − 0.26; 95% CI − 0.49 to − 0.04; P = 0.022), HL eBMD (Effect = − 0.09; 95% CI − 0.12 to − 0.06; P = 3.19 × 10–9), and total-body BMD in people aged 45–60 years (Effect = − 0.16; 95% CI − 0.31 to − 2.4 × 10–3; P = 0.047) and over 60 years (Effect = − 0.19; 95% CI − 0.33 to − 0.05; P = 0.006). Our study demonstrates that circulating SHBG concentrations are inversely associated with FA and HL eBMD, and total-body BMD in people aged over 45 years, suggesting that the role of SHBG in the development of osteoporosis might be affected by chronological age of patients and skeletal sites.

To find out the genetic association between IL6 and autoimmune arthritis. We performed a two-sample Mendelian randomization (MR) study using multiple genome-wide association studies (GWAS) datasets. Furthermore, a sex-stratified MR study was performed to identify sexual dimorphism in the association between IL6 and autoimmune arthritis. Then, LocusZoom plots were displayed based on the IL6R gene region to present evidence of genetic colocalization between diseases. The MR result denoted a genetic association between the increased level of IL-6 signaling and risk of RA (β=0.325, 95%CI 0.088, 0.561, p=7.08E-03) and AS (β=1.240, 95%CI 0.495, 1.980, p=1.1E-03). Accordingly, sIL6R was found to have negatively correlation with the onset of RA (β=-0.020, 95%CI -0.0320, -0.008, p=1.18E-03) and AS (β=-0.125, 95%CI -0.177, -0.073, p=2.29E-06). However, no genetic association between IL6/sIL6R and PsA was detected. The gender-stratified MR analysis showed that IL6 was associated with AS in the male population, with RA in the female population, and with PsA in the male population. Additionally, ADAR, a gene identified by a sensitive test, could be the reason for the nonsignificant association between IL6 and PsA in a pooled population. Our findings showed that the overactive IL6 signal pathway led to autoimmune arthritis, especially in RA and AS. Sexual difference was also observed in IL6-intermediate susceptibility to autoimmune arthritis.