Background: Rotator cuff tears are common, affecting more than 60% of individuals older than 80 years, and they have been implicated in 70% of patients with shoulder pain. M1 polarization-related inflammation has been reported to be associated with poor healing outcomes of rotator cuff injury, and leptin, an adipokine, has been reported to be a potential activator of inflammation. However, whether leptin affects rotator cuff repair remains unknown. Questions/purposes: Using in vitro cell experiments and an in vivo rat rotator cuff tear model, we therefore asked: (1) Does leptin promote the M1 polarization of macrophages in vitro and in vivo? (2) Does leptin impair biomechanical strength, the histologic structure of the tendon-bone interface, bone mineral density (BMD), or gait in the rotator cuff tear scenario? (3) Does leptin promote M1 polarization by upregulating the tumor necrosis factor (TNF) pathway? Methods: The impact of leptin on M1 macrophage polarization in vitro was determined by reverse transcription–polymerase chain reaction (RT-PCR), the Western blot test, and immunofluorescence staining. The effect of leptin on tendon-bone healing was assessed in an in vivo rat rotator cuff tear model by comparing a leptin group with a suture group in terms of gait, biomechanical tensile strength, the histologic structure of the tendon-bone interface, and BMD. In the in vivo experiments, 8-week-old male Sprague Dawley rats were used, adapting a previously developed rat rotator cuff tear model. The supraspinatus tendon was resected from the greater tuberosity bilaterally, and then the tendon was secured to its anatomical footprint using the transosseous single-row technique. In total, 30 rats were randomized into two groups (suture, leptin) by drawing lots (15 rats in each group). They were assessed at 2, 4, and 8 weeks after the surgery. In the suture group, 100 µL of normal saline was injected into the subacromial space after the deltoid muscle was restitched to the original position. In the leptin group, 100 µL of leptin solution (200 ng/mL) was injected into the subacromial space after the deltoid muscle was restitched to the original position. Biomechanical properties including maximal failure load, stiffness, and tensile failure stress were determined to assess the biomechanical strength at 4 and 8 weeks after the surgery. Histologic staining was conducted to compare the structure of the tendon-bone interface between treatment groups. Micro-MRI and micro-CT assessments were conducted to compare the overall healing outcome and BMD between treatment groups. Gait analysis was conducted to compare the stride length and strength between treatment groups. M1 macrophage polarization in vivo at the tendon-bone interface was assessed by immunofluorescence staining. Finally, to explore the underlying mechanism of the effects of leptin, Necrostatin-1 (Nec-1) was used to block the TNF signaling pathway in the in vitro macrophage study, and RT-PCR and Western blot were used to explore the underlying mechanism. Results: Leptin enhanced LPS-induced M1 polarization of macrophages in vitro, showing increased gene expression of CD86, Nos2, and TNF-α as well as increased protein expression of CD86, TNF-α, interleukin-6 (IL-6), and inducible NO synthase (iNOS). The in vivo polarization showed that the M1 polarization of macrophages at the tendon-bone interface was promoted. At 2 weeks postoperatively, there were more M1 cells in the leptin group (53 ± 5 versus 77 ± 8, mean difference 24 [95% confidence interval (CI) 11 to 37]; p = 0.002), although the proportion of M1 cells (ratio of the number of M1 cells to the total number of macrophages) was not higher (18.6% ± 2.9% versus 21.5% ± 1.7%, mean difference 2.9% [95% CI -2.8% to 8.7%]; p = 0.36). At 4 weeks postoperatively, the leptin group exhibited more M1 cells (31 ± 4 versus 50 ± 6, mean difference 19 [95% CI 6 to 32]; p = 0.008) and at a higher proportion (16.4% ± 2.6% versus 23.0% ± 3.0%, mean difference 6.6% [95% CI 0.8% to 12.4%]; p = 0.03). The in vivo experiments showed that leptin impaired tendon-bone healing. At 4 weeks postoperatively, the biomechanical properties of both groups were not different in terms of maximal failure load (12.7 ± 1.6 N versus 12.4 ± 1.8 N, mean difference -0.3 N [95% CI -2.6 to 1.8]; p = 0.91), stiffness (5.1 ± 0.7 N/mm versus 4.6 ± 0.8 N/mm, mean difference -0.5 N/mm [95% CI -1.3 to 0.5]; p = 0.44), and tensile failure stress (2.0 ± 0.3 N/mm² versus 2.0 ± 0.3 N/mm², mean difference 0.0 N/mm² [95% CI -0.4 to 0.4]; p = 0.99). At 8 weeks postoperatively, the leptin group showed worse maximal failure load (17.6 ± 1.4 N versus 14.1 ± 1.4 N, mean difference -3.5 N [95% CI -5.7 to -1.3]; p = 0.002), stiffness (7.0 ± 0.6 N/mm versus 5.2 ± 0.6 N/mm, mean difference -1.8 N/mm [95% CI -2.7 to -0.9]; p < 0.001), and tensile failure stress (3.4 ± 0.3 N/mm² versus 2.8 ± 0.4 N/mm², mean difference -0.6 N/mm² [95% CI -1.0 to -0.2]; p = 0.007). Results of histologic staining, image assessments, and gait analysis also demonstrated that leptin impaired the healing process. In vitro experiments showed that leptin upregulated the gene expression of molecules in the TNF pathway, including CCL2 and receptor-interacting protein kinase 1 (RIPK1), and M1 markers, such as TNF-α, CD86, and Nos2; the addition of Nec-1 neutralized the effect of leptin on macrophage polarization, reducing the expression of M1 markers, including TNF-α, CD86, and Nos2, and blocking the TNF signaling pathway, including CCL2 and RIPK. The protein expression exhibited similar trends. Conclusion: Based on the results of this study, leptin appears to impair tendon-bone healing in a rat model of rotator cuff tear, promote M1 macrophage polarization at the tendon-bone interface, and upregulate the TNF signaling pathway in macrophages to promote M1 polarization. Clinical Relevance: Obesity and fatty infiltration of the rotator cuff muscle are associated with poor healing of rotator cuff tears. In this study, the effect of leptin, an adipose factor, on tendon-bone healing and the underlying mechanism were explored. Future studies might focus on developing novel approaches to improve the tendon-bone healing in patients with obesity by targeting leptin or the TNF signaling pathway with the aid of biomaterials.

Purpose: Surgical options for long head of the biceps tendon (LHBT) lesions include tenotomy and tenodesis. This study aims to determine the optimal surgical strategy for LHBT lesions with updated evidence from randomised controlled trials (RCTs). Methods: Literature was retrieved from PubMed, Cochrane Library, Embase and Web of Science on 12 January 2022. Randomised controlled trials (RCTs) comparing the clinical outcomes of tenotomy and tenodesis were pooled in the meta-analyses. Results: Ten RCTs with 787 cases met the inclusion criteria, and were included in the meta-analysis. Constant scores (MD, −1.24; p = 0.001), improvement of Constant scores (MD, −1.54; p = 0.04), Simple Shoulder Test (SST) scores (MD, −0.73; p = 0.03) and improvement of SST (p < 0.05) were significantly better in patients with tenodesis. Tenotomy was associated with higher rates of Popeye deformity (OR, 3.34; p < 0.001) and cramping pain (OR, 3.36; p = 0.008]. No significant differences were noticed between tenotomy and tenodesis regarding pain (p = 0.59), American Shoulder and Elbow Surgeons (ASES) score (p = 0.42) and its improvement (p = 0.91), elbow flexion strength (p = 0.38), forearm supination strength (p = 0.68) and range of motion of shoulder external rotation (p = 0.62). Subgroup analyses showed higher Constant scores in all tenodesis types and significantly larger improvement of Constant scores regarding intracuff tenodesis (MD, −5.87; p = 0.001). Conclusions: According to the analyses of RCTs, tenodesis better improves shoulder function in terms of Constant scores and SST scores, and reduces the risk of Popeye deformity and cramping bicipital pain. Intracuff tenodesis might offer the best shoulder function as measured with Constant scores. However, tenotomy and tenodesis provide similar satisfactory results for pain relief, ASES score, biceps strength and shoulder range of motion.

Background: One-stage treatment involving rotator cuff repair and shoulder capsule release is mainly used to treat patients with rotator cuff tears (RCTs) and concomitant shoulder stiffness. Despite the increasing attention to the efficacy and safety of one-stage treatment, controversy still remains. Therefore, this systematic review aims to summarize the indications, operation procedure and rehabilitation protocol, and compare the range of motions (ROMs), functional outcomes and retear rates of one-stage treatment for RCTs in stiff shoulders and non-stiff shoulders. Methods: Multiple databases (PubMed, the Cochrane Library, Embase and MEDLINE) were searched for studies that investigated outcomes after one-stage treatment for RCTs concomitant with shoulder stiffness compared with rotator cuff repair for RCTs alone, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Descriptive statistics, including range of motion, patient-reported outcome and retear rate, are presented without meta-analysis due to the heterogeneity and low levels of evidence. Results: A total of 9 cohort studies were included, with 305 patients treated with one-stage treatment involving rotator cuff repair and simultaneous shoulder capsular release and 1059 patients treated with rotator cuff repair alone. Patients in both groups had significant symptom improvement and functional recovery after the one-stage treatment for the stiffness group and standard repair for the non-stiffness group, and most patients could return to normal life and work within 6 months after the operation. The retear rate in the one-stage treatment group was not higher than that in the rotator cuff repair group. No statistically significant differences between the two groups were observed in terms of range of motion and patient-reported outcomes in the vast majority of studies at the final follow-up, including the visual analog scale for pain, the Constant score, the American Shoulder and Elbow Surgeons score, the University of California Los Angeles Shoulder Score, the Oxford shoulder score and the Simple Shoulder Test. Conclusion: One-stage treatment for RCTs in stiff shoulders provides comparable ROM and patient-reported clinical outcomes as rotator cuff repair for non-stiff RCTs. In addition, the rate of postoperative retear in stiff shoulder treated with one-stage treatment was not higher than in non-stiff shoulders.

Degenerative musculoskeletal diseases (DMDs), including osteoarthritis, osteoporosis, sarcopenia, and intervertebral disc degeneration, are highly prevalent age-related conditions characterized by progressive tissue dysfunction and loss of musculoskeletal integrity. Aging is accompanied by profound alterations in organelle homeostasis, metabolic signaling, and stress adaptation, among which mitochondria-endoplasmic reticulum communication has emerged as a critical regulatory axis. Mitochondria-associated membranes (MAMs) are specialized contact sites that spatially and functionally couple the endoplasmic reticulum and mitochondria, thereby coordinating calcium signaling, redox balance, lipid metabolism, and cell fate decisions. Accumulating evidence indicates that aging-related disruption of MAMs integrity and signaling contributes to mitochondrial dysfunction, oxidative stress, aberrant stress responses, and inflammatory activation across multiple musculoskeletal tissues. In this review, we synthesize current evidence linking MAMs-associated signaling pathways-including calcium flux, reactive oxygen species regulation, unfolded protein response signaling, autophagy, inflammasome activation, and regulated cell death-to the pathogenesis of major degenerative musculoskeletal diseases. We further highlight shared and tissue-specific mechanisms through which age-dependent MAMs dysregulation drives musculoskeletal degeneration. By framing MAMs as aging-sensitive signaling hubs, this review provides an integrated perspective on how organelle crosstalk contributes to degenerative musculoskeletal diseases and identifies conceptual frameworks for understanding disease convergence during musculoskeletal aging.