Search

Background: Previous studies have shown that dyslipidemia is significantly associated with primary frozen shoulder and may be a risk factor for the development of primary frozen shoulder. However, these findings may be biased by a number of confounding factors. We investigated the association between serum lipids and primary frozen shoulder by retrospective analysis and two-sample Mendelian randomization (MR) methods., Methods: This retrospective observational study included 284 patients with primary frozen shoulder diagnosed from October 2020 to October 2023 at four centers as the experimental group. Patients with diabetes and thyroid dysfunction were excluded. The control group consisted of age- and sex-matched people who underwent a health checkup. We compared total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) between the two groups. Genetic variants for the serum lipids and frozen shoulder were then extracted from large-scale genome-wide association studies. Causal effects were assessed using Inverse variance weighting (IVW), Weighted median, MR-Egger, simple and weighted models in MR analysis., Results: The analysis showed that after excluding patients with diabetes and thyroid dysfunction, the serum lipids (TC, TG, HDL, and LDL) in the primary frozen shoulder group were no different from those of normal individuals. None of the MR methods found significant causal evidence between them., Conclusions: Dyslipidemia in patients with primary frozen shoulder may be influenced by confounding factors such as diabetes and thyroid dysfunction. These findings deepen our understanding of primary frozen shoulder risk factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Zhang, Fan, Wang, Dong, Liu and Shao.)

A Mendelian randomization (MR) study was undertaken to establish a causal link between gastroesophageal reflux disease (GERD) and frozen shoulder (FS), examining whether the risk of GERD with FS is mediated through mood fluctuations. Genetic loci from populations of independent European ancestry were selected as instrumental variables for GERD, FS, and mood swings. The primary analysis employed the inverse-variance weighted method supplemented by 3 additional analytical methods. This was conducted using two-sample and two-step MR analyses. This study explored the correlation and mediating effects of mood swings between GERD and FS. Our study employed heterogeneity and horizontal diversity, and sensitivity analysis was conducted using the leave-one-out method to explore the robustness of the results. In the two-sample MR analysis, for every 1-unit increase in the log-transformed odds ratio (OR) of GERD, the corresponding OR increased to 1.844 (inverse-variance weighting: OR = 1.844, 95% confidence interval: 1.47-2.30, P < .001). In the two-step MR analysis, we found that mood swings played a mediating role in the association between GERD and FS. We assessed this mediating effect using the delta method (b = 0.181, SE = 0.059, OR = 1.199, 95% confidence interval: 1.072-1.349). Analysis of the data using the above methods indicated that GERD is a risk factor for FS, and mood swings mediate between the 2. Therefore, GERD and mood swings should be included in the health management of patients with FS., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Although existing studies have indicated a connection between chronic low-grade inflammation and the onset of frozen shoulder (FS), the precise causal relationship between distinct circulating inflammatory factors and FS has yet to be thoroughly evaluated. In this study, we employed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between systemic cytokines and FS., Methods: A genome-wide association dataset comprising 41 serum cytokines from 8,293 individuals of Finnish descent was utilized, along with FS data from the UK Biobank included 10,104 FS cases and 451,099 controls. The primary MR method was the inverse variance weighted approach, and four additional MR techniques (MR-Egger, weighted median, simple mode, and weighted mode) were also employed to support and validate the findings. Heterogeneity and horizontal pleiotropy assessments were assessed using Cochrane's Q and MR-Egger intercept tests. Moreover, a series of sensitivity analyses were conducted to strengthen the accuracy and credibility of these findings., Results: Based on the IVW method, genetically predicted increasing levels of growth regulated oncogene alpha (GROa) (OR=1.08, 95 % CI 1.02-1.13, P=0.005), interferon gamma-induced protein 10 (IP-10) (OR=1.09, 95 % CI 1.02-1.17, P=0.010), regulated on activation, C-C Motif Chemokine Ligand 5 (CCL5) (OR=1.11, 95 % CI 1.03-1.20, P=0.007) were suggestively associated with an increased risk of FS. Reverse MR analysis revealed no significant causal effect of FS on the 41 systemic inflammatory factors. No heterogeneity or horizontal pleiotropy was observed in our analysis., Conclusion: This study established a causal association between 41 systemic inflammatory factors and FS, indicating that elevated levels of GROa, IP-10 and CCL5 were associated with a higher risk of FS. Further research is warranted to explore the potential of these biomarkers as early predictors and therapeutic targets for FS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

The pathogenesis of frozen shoulder (FS) remains unclear, and current research primarily focuses on immune responses. Increasing evidence suggests that immune cells play a significant role in FS development. However, the causal relationship between the two remains poorly understood. Therefore, we aimed to investigate this using Mendelian randomization (MR) analysis. Single nucleotide polymorphisms closely associated with 731 immune phenotypes were obtained from publicly available GWAS datasets as instrumental variables. FS was used as the outcome with a sample size of 451,099 cases. Causal effects were analyzed using the inverse variance-weighted method. We conducted sensitivity tests, including the intercept of the MR-Egger and MR-PRESSO analyses. The presence of heterogeneity was evaluated using Cochran Q test. We identified potential causal relationships in terms of increased risk for FS with 5 immune phenotypes: CD25++ CD45RA+ CD4 not regulatory T cell %CD4+ T cells (odds ratio [OR] = 1.0273, 95% confidence interval [CI]: 1.0093-1.0457, P = .0028), CD25++ CD45RA+ CD4 not regulatory T cell %T cell (OR = 1.0240, 95% CI: 1.0057-1.0427, P = .0098), CD127 on CD28+ CD4+ T cells (OR = 1.0398, 95% CI: 1.0121-1.0682, P = .0046), CD4 on human leukocyte antigen DR+ CD4+ T cells (OR = 1.0795, 95% CI: 1.0316-1.2195, P = .0009), and human leukocyte antigen DR on CD14- CD16+ monocytes (OR = 1.0533, 95% CI: 1.0136-1.0945, P = .0081). Few significant heterogeneities or horizontal pleiotropies were observed. Through MR analysis, we identified distinct 5 types of immune cells that were positively correlated with the occurrence and development of FS, providing guidance for clinical intervention in FS., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Frozen shoulder (FS) is characterized by the thickening and fibrosis of the joint capsule, leading to joint contracture and a reduction in joint volume. The precise etiology responsible for these pathological changes remains elusive. Therefore, the primary aim of this study was to explore the potential involvement of pathogenic genes in FS and analyze their underlying roles in the disease progression. Methods: Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to investigate co-expressed genes potentially associated with FS. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to elucidate the potential roles of these co-expressed genes. Subsequently, Mendelian randomization (MR) analysis was performed using expression quantitative trait loci datasets for the co-expressed genes, combined with summary statistics from the genome-wide association study of FS, aiming to identify key genes causally associated with FS. The identified key genes were further validated through reverse transcription-quantitative PCR (RT-qPCR). Additionally, a nomogram model and receiver operating characteristic (ROC) curves were established to assess the diagnostic value of the hub genes. Furthermore, the infiltration of immune cells was evaluated using the CIBERSORT algorithm and the relationship between key genes and immune-infiltrating cells was analyzed. Results: 295 overlapping co-expressed genes were identified by intersecting the differentially expressed genes with the hub genes obtained from associated modules identified through WGCNA. Utilizing MR analysis, four key genes, namely ADAMTS1, NR4A2, PARD6G and SMKR1, were found to exhibit positive causal relationships with FS, which were subsequently validated through RT-qPCR analysis. Moreover, the diagnostic value of these four key genes was demonstrated through the development of a nomogram model and the construction of ROC curves. Notably, a causal relationship between ADAMTS1 and immune cell infiltration in FS was observed. Conclusion: Our study suggested genetic predisposition to higher expression levels of ADAMTS1, NR4A2, PARD6G and SMKR1, was associated with an increased risk of FS. Further investigations elucidating the functional roles of these genes will enhance our understanding of the pathogenesis of FS and may facilitate the development of targeted treatment strategies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: Frozen shoulder is a common shoulder disease that significantly affects the patient's life and work. Ferroptosis is a new type of programmed cell death, which is involved in many diseases. However, there have been no studies reporting the relationship between frozen shoulders and ferroptosis. This study identified potential molecular markers of ferroptosis in frozen shoulders to provide more effective strategies for the treatment of frozen shoulders., Methods: GSE238053 was downloaded from the Gene Expression Omnibus (GEO) dataset and intersected with ferroptosis genes to obtain differentially expressed genes (DEGs). The signaling pathways and biological functions of DEGs were performed by WebGestalt and Metascape. The interactions related to these DEGs and the key genes between frozen shoulders and ferroptosis was performed by STRING and Cytoscape. A frozen shoulders rat model was used to validate our predicted genes, Western Blot and qRT-PCR was used to assess the expression levels of our genes of interest., Results: A total of 34 DEGs between GSE238053 and Ferroptosis Database were obtained, most of which were involved in the HIF-1 signaling pathway and inflammatory response. A protein-protein interaction network was obtained by Cytoscape and the key genes (IL-6, HMOX1 and TLR4) were screened by MCODE. Our results of Western Blot showed that the protein expression level of TLR4 and HMOX1 were elevated, and the protein level of IL-6 decreased in frozen shoulders rat model. The mRNA level after frozen shoulders showed that IL-6 was upregulated, whereas TLR4 and HMOX1were downregulated., Conclusions: The results demonstrated that ferroptosis may affect the pathological process of frozen shoulders through these signaling pathways and genes. The identification of IL-6, HMOX1 and TLR4 genes can provide new therapeutic targets for frozen shoulders., (© 2024. The Author(s).)

Background: Many studies have investigated the association between hypothyroidism and frozen shoulder, but their findings have been inconsistent. Furthermore, earlier research has been primarily observational, which may introduce bias and does not establish a cause-and-effect relationship. To ascertain the causal association, we performed a two-sample bidirectional Mendelian randomization (MR) analysis., Methods: We obtained data on "Hypothyroidism" and "Frozen Shoulder" from Summary-level Genome-Wide Association Studies (GWAS) datasets that have been published. The information came from European population samples. The primary analysis utilized the inverse-variance weighted (IVW) method. Additionally, a sensitivity analysis was conducted to assess the robustness of the results., Results: We ultimately chose 39 SNPs as IVs for the final analysis. The results of the two MR methods we utilized in the investigation indicated that a possible causal relationship between hypothyroidism and frozen shoulder. The most significant analytical outcome demonstrated an odds ratio (OR) of 1.0577 (95% Confidence Interval (CI):1.0057-1.1123), P = 0.029, using the IVW approach. Furthermore, using the MR Egger method as a supplementary analytical outcome showed an OR of 1.1608 (95% CI:1.0318-1.3060), P = 0.017. Furthermore, the results of our sensitivity analysis indicate that there is no heterogeneity or pleiotropy in our MR analysis. In the reverse Mendelian analysis, no causal relationship was found between frozen shoulders and hypothyroidism., Conclusion: Our MR analysis suggests that there may be a causal relationship between hypothyroidism and frozen shoulder., (© 2024. The Author(s).)

Background: Mounting evidence suggests a connection between inflammatory cytokines and adhesive capsulitis (AC). However, the specific systemic inflammatory cytokines contributing to AC have not been clearly identified. This study employed Mendelian randomization (MR) to explore the causal relationships between 41 inflammatory cytokines and AC., Methods: In this bidirectional, two-sample MR analysis, genetic variations associated with AC were derived from a comprehensive genome-wide association study (GWAS). The inflammatory cytokines data were sourced from a GWAS summary involving 8,293 healthy participants. The primary MR method employed was inverse variance weighting, supplemented by MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier for sensitivity analysis. Heterogeneity was assessed using Cochran's Q test, and the MR results were validated using the leave-one-out method., Results: Elevated levels of interferon gamma-induced protein 10 (IP-10) (odds ratio (OR) = 1.086, 95% confidence interval (CI) = 1.002-1.178) and regulated on activation, normal T cell expressed and secreted (RANTES) (OR = 1.107, 95% CI = 1.026-1.195) were linked to an increased risk of AC. Increased levels of stromal cell-derived factor-1 alpha (SDF-1α) (OR = 0.879, 95% CI = 0.793-0.974) and tumor necrosis factor-alpha (TNF-α) (OR = 0.911, 95% CI = 0.831-0.999) were associated with a reduced AC risk. Moreover, genetically predicted AC exhibited associations with elevated cutaneous T cell attracting (CTACK) levels (OR = 1.202, 95% CI = 1.007-1.435) and diminished levels of interleukin-17 (IL-17) (OR = 0.678, 95% CI = 0.518-0.888) and interleukin-5 (IL-5) (OR = 0.786, 95% CI = 0.654-0.944), as confirmed through inverse-variance weighted (IVW) methods., Conclusion: The present study successfully establishes a causal association between genetically proxied circulating levels of IP-10, RANTES, SDF-1α, and TNF-α and the risk of AC. Additionally, AC contributes to an increase in CTACK and a decrease in IL-17 and IL-5. This significant finding not only enhances the understanding of the pathogenesis of AC but also holds promise for the development of effective clinical management strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ouyang and Dai.)

The study aimed to explore the pathogenesis of secondary frozen shoulder and its influence on synovium tissue and angiogenesis by constructing a rat secondary frozen shoulder model along with transforming growth factor. 40 healthy male rats aged 8 weeks were divided into Sham group (n=10, no modeling treatment), Control group (n=10, modeling treatment), Low group (n=10, modeling treatment, and 10 mL/d transforming growth factor), and High group (n=10, modeling treatment, and 20 mL/d transforming growth factor). Hematoxylin and Eosin (HE) method was used for histological detection, and Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and immunohistochemical staining method were adopted to detect the expression of Matrix metalloproteinase-14 (MMP-14), mitogen-activated protein kinase (p38MAPK), and Vascular endothelial growth factor (VEGF). Compared with Sham group, the range of abduction and external rotation of rat glenohumeral joint in Control group, Low group, and High group was significantly reduced, and High group had the smallest range. Compared with the Sham group, the synovium in the Control group, the Low group, and the High group had obvious hyperplasia, and the blood vessels were significantly increased. Immunohistochemical staining and RT-PCR results showed that compared with Sham group, MMP-14, p38 MAPK, and VEGF in Control group, Low group, and High group all increased significantly, among which High group increased most. The secondary frozen shoulder is mainly manifested as synovial hyperplasia and increased blood vessels, which are related to the induction of MMP-14, p38 MAPK, and VEGF by transforming growth factor, which reveals the pathogenesis of secondary frozen shoulder to a certain extent, and lays a foundation for subsequent clinical treatment of secondary frozen shoulder.

Multiple studies have indicated a potential correlation between immune-mediated inflammatory diseases (IMIDs) and Frozen shoulder (FS). To explore the genetic causal relationship between IMIDs and FS using 2-sample Mendelian randomization (MR) analysis. Genome-wide association study (GWAS) summary data for FS were obtained from Green's study, while data for 10 IMIDs were sourced from the FinnGen Consortium. The MR analysis was performed using inverse variance weighting, MR Egger, and weighted median methods. IVW, as the primary MR analysis technique, was complemented with other sensitivity analyses to validate the robustness of the results. Additionally, reverse MR analysis was further conducted to investigate the presence of reverse causal relationships. In the forward MR analysis, genetically determined 4 IMIDs are causally associated with FS: rheumatoid arthritis (odds ratio [OR] (95% confidence interval [95% CI]) = 1.05 [1.02-1.09], P < .01); type 1 diabetes (OR [95% CI] = 1.06 [1.03-1.09], P < .01); hypothyroidism (OR [95% CI] = 1.07 [1.01-1.14], P = .02); and Celiac disease (OR [95% CI] = 1.02 [1.01-1.04], P = .01). However, no causal relationship was found between 6 IMIDs (autoimmune hyperthyroidism, Crohn disease, ulcerative colitis, psoriasis, sicca syndrome and systemic lupus erythematosus) and FS. Sensitivity analyses did not detect any heterogeneity or horizontal pleiotropy. In the reverse MR analysis, no causal relationship was observed between FS and IMIDs. In conclusion, this MR study suggests a potential causal relationship between rheumatoid arthritis, type 1 diabetes, hypothyroidism, and Celiac disease in the onset and development of FS. Nevertheless, more basic and clinical research will be needed in the future to support our findings., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: This study aimed to assess the causal relationship between diabetes and frozen shoulder by investigating the target proteins associated with diabetes and frozen shoulder in the human plasma proteome through Mendelian randomization (MR) and to reveal the corresponding pathological mechanisms., Research Design and Methods: We employed the MR approach for the purposes of establishing: (1) the causal link between diabetes and frozen shoulder; (2) the plasma causal proteins associated with frozen shoulder; (3) the plasma target proteins associated with diabetes; and (4) the causal relationship between diabetes target proteins and frozen shoulder causal proteins. The MR results were validated and consolidated through colocalization analysis and protein-protein interaction network., Results: Our MR analysis demonstrated a significant causal relationship between diabetes and frozen shoulder. We found that the plasma levels of four proteins were correlated with frozen shoulder at the Bonferroni significance level (p<3.03E-5). According to colocalization analysis, parathyroid hormone-related protein (PTHLH) was moderately correlated with the genetic variance of frozen shoulder (posterior probability=0.68), while secreted frizzled-related protein 4 was highly correlated with the genetic variance of frozen shoulder (posterior probability=0.97). Additionally, nine plasma proteins were activated during diabetes-associated pathologies. Subsequent MR analysis of nine diabetic target proteins with four frozen shoulder causal proteins indicated that insulin receptor subunit alpha, interleukin-6 receptor subunit alpha, interleukin-1 receptor accessory protein, glutathione peroxidase 7, and PTHLH might contribute to the onset and progression of frozen shoulder induced by diabetes., Conclusions: Our study identified a causal relationship between diabetes and frozen shoulder, highlighting the pathological pathways through which diabetes influences frozen shoulder., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

To investigate the causal relationship between dried fruit intake and frozen shoulder using Mendelian randomization (MR). Genome wide association studies were conducted to pool data and select genetic loci independently associated with dried fruit intake and frozen shoulder in people of European ancestry as instrumental variables. Three MR analyses, inverse variance weighting, weighted median and MR-Egger, were used to investigate the causal relationship between dried fruit intake and frozen shoulder. Heterogeneity and multiplicity tests were used, and sensitivity analyses were conducted using the leave-one-out method to explore the robustness of the results. The inverse variance weighting results showed an OR (95 % CI) of 0.52 (0.34-0.80), P = .003, suggesting that there is a causal relationship between dried fruit intake and frozen shoulder. And no heterogeneity and multiplicity were found by the test and sensitivity analysis also showed robust results. The present study used a two-sample MR analysis, and by analyzing and exploring the genetic data, the study showed that too little intake of dry fruits is a risk factor for developing frozen shoulder., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

To investigate the causal relationship between hypothyroidism and frozen shoulder using a Mendelian randomization (MR) approach. Pooled data from a large-scale genome-wide association study (GWAS) were used. Genetic loci that were independent of each other and associated with hypothyroidism and frozen shoulder in populations of European ancestry were selected as instrumental variables. Inverse variance weighting (IVW) was used as the primary analysis method. Weighted median (WME) and MR-Egger were used as complementary analysis methods to assess causal effects. To explore the causal relationship between hypothyroidism and frozen shoulder. Sensitivity test analysis was performed using heterogeneity test, multiple validity test, and leave-one-out analysis to explore the robustness of the results. IVW results showed an OR (95% CI) of 1.07 (1.01-1.14), P = .024, indicating that hypothyroidism is a risk factor for a frozen shoulder. And no pleiotropy was found by the test, and sensitivity analysis also showed robust results. This study used 2-sample MR analysis to analyze and explore the genetic data, and the results showed a higher prevalence of frozen shoulder in patients with hypothyroidism, suggesting that active control of hypothyroidism may reduce the occurrence of frozen shoulder., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: This study aims to explore the mechanism of miR-211-5p in extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (BMSCs) in improving frozen shoulder (FS) in rat models., Methods: Rat BMSCs and EVs derived from rat BMSCs were isolated, identified, and then injected into rats to assess the expression of TGF-β, MMP1, MMP3, MMP12, GAP43, and PGP9.5 in shoulder capsule tissues. The range of motion of bilateral glenohumeral joints was assessed and pathological changes of shoulder capsule tissues were observed after hematoxylin-eosin staining. The binding sites of miR-211-5p to KDM2B and LACC1 to H3K4me3 were measured. FS rat models with LACC1 highly expressed were established to assess the motion of bilateral glenohumeral joints and expression of arthritis related factors in rats., Results: EVs were successfully extracted from BMSCs. Injection of BMSCs-EVs could improve the activity of bilateral glenohumeral joints and the pathological condition of joint capsule in rats. Elevated expression of miR-211-5p was found in rats injected with BMSCs-EVs. Dual luciferase assay showed that miR-211-5p had a binding site with KDM2B. ChIP, qRT-PCR, and western blot experiments showed BMSCs-EVs injection resulted in elevated enrichment of LACC1 promoter in shoulder capsule tissues of FS rats, and decreased mRNA and protein expression of KDM2B and increased H3K4me3 methylation. Overexpression of LACC1 could also improve the pathological condition of joint capsule tissue., Conclusion: miR-211-5p in EVs derived from BMSCs increased H3K4me3 methylation in shoulder capsule tissue of rats by binding KDM2B, resulting in up-regulated transcription level of LACC1 and improving FS., Availability of Data and Materials: The datasets used or analyzed during the current study are available from the corresponding author on reasonable request., Competing Interests: Conflict of interests The authors declare there is no conflict of interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The etiology of adhesive capsulitis involves inflammation, thickening, and fibrosis of the shoulder capsule. The underlying genetic factors are poorly understood. The purpose of this study was to identify genetic variants associated with adhesive capsulitis using the UK Biobank (UKB) cohort and compare them with variants associated with Dupuytren disease investigating a common etiology between the 2 fibrotic disorders., Methods: A genome-wide association study (GWAS) was performed using data from UKB with 10,773 cases of adhesive capsulitis, and a second GWAS was performed with 8891 cases of Dupuytren disease. Next, a comparison of association statistics was performed between adhesive capsulitis and Dupuytren disease using the data from both GWAS. Finally, single-nucleotide polymorphisms (SNPs) previously reported from candidate gene studies for adhesive capsulitis and Dupuytren disease were tested for association with adhesive capsulitis and Dupuytren disease using the summary statistics from their respective GWAS., Results: The UKB GWAS for adhesive capsulitis identified 6 loci that reached genome-wide statistical significance: a cluster of 11 closely linked SNPs on chromosome 1; a single SNP on chromosome 2; a single SNP on chromosome 14; 2 closely linked SNPs on chromosome 21; 33 closely linked SNPs on chromosome 22; and 3 closely linked SNPs on the X chromosome. These SNPs were associated with 8 different genes including TSPAN2/NGF, SATB2, MRPL52/MMP14, ERG, WNT7B, and FGF13. A GWAS for Dupuytren disease was performed and a comparison to the adhesive capsulitis GWAS showed 13 loci significantly associated with both phenotypes. A validation attempt of 6 previously reported SNPs associated with adhesive capsulitis using UKB summary statistics was unable to confirm any of the previously reported SNPs (all P > .19). All 23 previously reported SNPs associated with Dupuytren disease were confirmed using the UKB summary statistics (P < 2.1 × 10 -3 ) CONCLUSION: This GWAS investigating adhesive capsulitis has identified 6 novel loci involving 8 different genes to be associated with adhesive capsulitis. A GWAS investigating Dupuytren disease was performed and compared to the adhesive capsulitis GWAS, and 13 common loci were identified between the 2 disorders with genes involved in pathologic fibrosis. We were unable to validate the SNPs in candidate genes previously reported to be associated with adhesive capsulitis although we were able to confirm all previously reported SNPs associated with Dupuytren disease. The strong genetic overlap between the adhesive capsulitis and Dupuytren disease loci suggests a similar etiology between the 2 diseases., (Copyright © 2022 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: Adhesive capsulitis of the shoulder involves loss of passive range of motion with associated pain and can develop spontaneously, with no obvious injury or inciting event. The pathomechanism of this disorder remains to be elucidated, but known risk factors for adhesive capsulitis include diabetes, female sex, and thyroid dysfunction. Additionally, transcriptional profiling and pedigree analyses have suggested a role for genetics. Identification of elements of genetic risk for adhesive capsulitis using population-based techniques can provide the basis for guiding both the personalized treatment of patients based on their genetic profiles and the development of new treatments by identification of the pathomechanism., Methods: A genome-wide association study (GWAS) was conducted using the U.K. Biobank (a collection of approximately 500,000 patients with genetic data and associated ICD-10 [International Classification of Diseases, 10th Revision] codes), comparing 2,142 patients with the ICD-10 code for adhesive capsulitis (M750) to those without. Separate GWASs were conducted controlling for 2 of the known risk factors of adhesive capsulitis-hypothyroidism and diabetes. Logistic regression analysis was conducted controlling for factors including sex, thyroid dysfunction, diabetes, shoulder dislocation, smoking, and genetics., Results: Three loci of significance were identified: rs34315830 (in WNT7B; odds ratio [OR] = 1.28; 95% confidence interval [CI], 1.22 to 1.39), rs2965196 (in MAU2; OR = 1.67; 95% CI, 1.39 to 2.00), and rs1912256 (in POU1F1; OR = 1.22; 95% CI, 1.14 to 1.31). These loci retained significance when controlling for thyroid dysfunction and diabetes. The OR for total genetic risk was 5.81 (95% CI, 4.08 to 8.31), compared with 1.70 (95% CI, 1.18 to 2.36) for hypothyroidism and 4.23 (95% CI, 2.32 to 7.05) for diabetes., Conclusions: The total genetic risk associated with adhesive capsulitis was significant and similar to the risks associated with hypothyroidism and diabetes. Identification of WNT7B, POU1F1, and MAU2 implicates the Wnt pathway and cell proliferation response in the pathomechanism of adhesive capsulitis., Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H192 )., (Copyright © 2022 by The Journal of Bone and Joint Surgery, Incorporated.)

Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/H239).

Background: Severe frozen shoulder (FS) is often resistant to treatment and can thus result in long-term functional impairment. However, its etiology remains unknown. We hypothesized that gene expression of FS would vary by synovial location., Methods: The synovial tissues of patients with FS were collected prospectively and analyzed for the expression of 19 genes. Synovial tissues from patients with rotator cuff tear (RCT) or shoulder instability (SI) were also analyzed as controls. A total of 10 samples were analyzed from each group. The specimens were arthroscopically taken from three different locations: rotator interval (RI), axillary recess (AX), and subacromial bursa (SAB). Total RNA was extracted from the collected tissues and was analyzed by real-time polymerase chain reaction for the following genes: matrix metalloproteinases (MMPs); tissue inhibitors of metalloproteinases (TIMPs); inflammatory cytokines (IL1B, TNF, and IL6); type I and II procollagen (COL1A1 and COL2A1); growth factors (IGF1 and TGFB1); neural factors (NGF and NGFR); SOX9; and ACTA2., Results: Site-specific analysis showed that MMP13, IL-6, SOX9, and COL1A1 were increased in all three sites. Four genes (MMP3, MMP9, COL2A1, and NGFR) were increased in the AX, MMP3 in the RI, and NGFR in the SAB were increased in the FS group than in the RCT and SI groups. In the FS group, there was a correlation between the expression of genes related to chondrogenesis (MMP2, IGF1, SOX9, COL2A1, NGF, and NGFR) or fibrosis (MMP9, TGFB1, and COL1A1)., Conclusion: The expression levels of numerous MMPs, pro-inflammatory cytokines, and collagen-related genes were increased in the FS group, suggesting that catabolic and anabolic changes have simultaneously occurred. In addition, genes related to chondrogenesis or fibrosis were highly expressed in the FS group, which might have affected the range of motion limitation of the shoulder. Compared to RI and SAB, the AX was the most common site of increased expression in FS. Analyzing the lower region of the shoulder joint may lead to the elucidation of the pathogenesis of FS., (© 2022. The Author(s).)

Background: Diabetic patients have a greater incidence of adhesive capsulitis (AC) and a more protracted disease course than patients with idiopathic AC. The purpose of this study was to compare gene expression differences between AC with diabetes mellitus and AC without diabetes mellitus., Methods: Shoulder capsule samples were prospectively obtained from diabetic or nondiabetic patients who presented with shoulder dysfunction and underwent arthroscopy (N = 16). Shoulder samples of AC with and without diabetes (n = 8) were compared with normal shoulder samples with and without diabetes as the control group (n = 8). Shoulder capsule samples were subjected to whole-transcriptome RNA sequencing, and differential expression was analyzed with EdgeR. Only genes with a false discovery rate < 5% were included for further functional enrichment analysis., Results: The sample population had a mean age of 47 years (range, 24-62 years), and the mean hemoglobin A 1c level for nondiabetic and diabetic patients was 5.18% and 8.71%, respectively. RNA-sequencing analysis revealed that 66 genes were differentially expressed between diabetic patients and nondiabetic patients with AC whereas only 3 genes were differentially expressed when control patients with and without diabetes were compared. Furthermore, 286 genes were differentially expressed in idiopathic AC patients, and 61 genes were differentially expressed in diabetic AC patients. On gene clustering analysis, idiopathic AC was enriched with multiple structural and muscle-related pathways, such as muscle filament sliding, whereas diabetic AC included a greater number of hormonal and inflammatory signaling pathways, such as cellular response to corticotropin-releasing factor., Conclusions: Whole-transcriptome expression profiles demonstrate a fundamentally different underlying pathophysiology when comparing diabetic AC with idiopathic AC, suggesting that these conditions are distinct clinical entities. The new genes expressed explain the differences in the disease course and suggest new therapeutic targets that may lead to different treatment paradigms in these 2 subsets., (Copyright © 2021 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Objectives: Primary frozen shoulder (pFS) has three phases that differ in clinical presentation. It is characterized by contracture of the joint capsule. We hypothesized that there is a general upregulation of collagens in pFS, and that this is highest in the first phase of the disease. The aims of this study were to investigate the expression of various collagens and degradation of collagens in patients with primary pFS and relate this to the three phases of the condition., Methods: From twenty-six patients with pFS and eight control patients with subacromial impingement, biopsies were obtained during shoulder arthroscopy from the middle glenohumeral ligament and the anterior capsule, and mRNA levels for collagens, MMP-2 and -14 and TGF-β1, - β2 and -β3 in the tissue were analysed using real-time PCR., Results: Genes for collagens type I, III, IV, V, VI and XIV, were activated in pFS, and the total mRNA for all collagens was increased (P < 0.05). This upregulation was independent of disease phases in pFS. In addition, MMP-2, MMP-14, TGF-β1 and TGF-β3 were upregulated in all phases of the disease., Conclusion: There is a general upregulation and an increased degradation of collagens in pFS in all three phases of the disease. This indicates a constantly increased turnover of the fibrotic tissue in the capsule from pFS. The difference in clinical presentation of pFS observed in the three phases of the disease is not primarily a result of variations in collagen production., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40-60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes. We performed a genome-wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 10,104 cases identified from inpatient, surgical and primary care codes. We used data from FinnGen for replication and meta-analysis. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder. We identified five genome-wide significant loci. The most significant locus (lead SNP rs28971325; OR = 1.20, [95% CI: 1.16-1.24], p = 5x10-29) contained WNT7B. This variant was also associated with Dupuytren's disease (OR = 2.31 [2.24, 2.39], p<1x10-300) as were a further two of the frozen shoulder associated variants. The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR = 1.03 [1.02-1.05], p = 3x10-6). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects. We have identified genetic loci associated with frozen shoulder. There is a large overlap with Dupuytren's disease associated loci. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition., Competing Interests: The authors have declared that no competing interests exist.

Frozen shoulder is a condition of loss of active and passive motion as result of inflammatory contracture and fibrosis of the joint capsule. We hypothesize that genetic variants in genes involved in these processes such as genes that play a role in extracellular matrix homeostasis (collagens, glycoproteins, genes involved in TGFβ signaling, and metalloproteinases and its inhibitors) may contribute to the susceptibility to frozen shoulder. We evaluated eighteen SNPs of genes involved in extracellular matrix homeostasis in 186 cases (N females  = 114; N males  = 72) of frozen shoulder and 600 age-matched controls (N females  = 308; N males  = 292). Multivariate logistic regressions were carried out with age, gender, genetic ancestry, and common comorbidities as covariates. Carriers of the C allele of MMP13 rs2252070 and G/G MMP9 (rs17576 A>G/rs17577 G>A) haplotype may have an increased risk of frozen shoulder (p = 0.002, OR = 1.64, 95%CI = 1.20-2.26, and p = 0.046, OR = 1.40, 95%CI = 1.01-1.95, respectively), especially in females (p = 0.005, OR = 1.91, 95%CI = 1.22-2.99, and p = 0.046, OR = 1.59, 95%CI = 1.01-2.51, respectively). In females, the G allele of MMP9 rs17576 tended to contribute to the susceptibility to the studied disease (p = 0.05, OR = 1.51, 95%CI = 0.97-2.33). In contrast, the presence of the C allele of TGFB1 rs1800470 seems to be associated with a reduced risk (p = 0.04, OR = 0.47, 95%CI = 0.23-0.96) while the GG-genotype of TGFBR1 rs1590 was associated with increased risk (p = 0.027, OR = 4.11, 95%CI = 1.17-14.38) to frozen shoulder development in males. Thus, we identified genetic variants that were independent risk factors that can aid in the risk assessment of frozen shoulder reinforcing the involvement of MMP and TGFβ signaling in disease development. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Purpose: Relationship between shoulder adhesive capsulitis (AC) and hypercholesterolemia is known. The connecting link might be represented by the correlation between HDL and transforming growth factor beta (TGF-β): normally, HDLs stimulate TGF-β expression; the latter is employed in the development of fibrous tissue. We assess whether the presence of the Apo-A1-G75A-polymorphism, which is correlated to an enhanced HDL function, could be a risk factor for the genesis and severity of AC., Methods: Peripheral blood samples of 27 patients [7M; 20F, mean age 54.81 (41-65)] with AC and hypercholesterolemia were submitted to polymerase chain reaction in order to evaluate the Apo-A1-G75A-polymorphism. Genome database was used as control. Two categories were obtained according to AC severity: type I (active forward flexion ≥ 100°) and type II (< 100°). Data were submitted to statistics., Results: The prevalence of Apo-A1-G75A-polymorphism in the studied group and in the control group was 22.2% (10AG; 1AA; 16GG) and 19% (OR 1.22, IC 0.59-2.53, p > 0.05), respectively. Patients with type I and II capsulitis were 11 [flexion 148.0° (range 100°-165°)] and 16 [flexion 82.5° (range 50°-95°)], respectively. The prevalence of Apo-A1-G75A in type I was 18.1% (2AG; 9GG) and in type II was 56.3% (8GA; 1AA; 7GG), respectively (RR 1.87, IC 1.005-3.482, p < 0.05)., Conclusions: Apo-A1-G75A-polymorphism is not necessary for the genesis, but it is a risk factor for severity of AC., Level of Evidence: III.

Background: The etiology of frozen shoulder (FS) is unclear. Accordingly, this study used a label-free quantitative shotgun proteomic approach to elucidate the pathogenesis of FS based on protein expression levels., Methods: Tissue samples from the rotator interval (RI), middle glenohumeral ligament (MGHL), and anterior-inferior glenohumeral ligament (IGHL) were collected from 12 FSs with severe stiffness and 7 shoulders with a rotator cuff tear (RCT) as controls. Protein mixtures were digested and analyzed by nano-liquid chromatography/electrospray ionization-tandem mass spectrometry. Relative protein expression levels were calculated by the signal intensity of identified peptide ions on mass spectra. Differentially expressed proteins between FS and RCT samples were evaluated by a gene enrichment analysis using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes., Results: We identified 1594 proteins, 1358 of which were expressed in all 6 tissue groups. We detected more upregulated proteins in the upper (RI and MGHL) FS groups and the lower (IGHL) RCT group than in the comparative groups, respectively. Various proteins with functions in tissue repair, collagen metabolism and fibrillation, cell-cell and cell-matrix adhesion, blood coagulation, and the immune response were expressed more highly in the RI and MGHL FS groups than in the RCT group. Proteins with functions in phagocytosis, glutathione metabolism, retinoid metabolism, and cholesterol metabolism were expressed more highly in the IGHL RCT group than in the FS group., Conclusions: The pathophysiology of FS differs between the upper and lower parts of the joint capsule. Different treatment strategies for FS may be appropriate, depending on the location., (Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

The present study aimed to investigate idiopathic adhesive capsulitis (frozen shoulder), to gain insights on its pathogenesis, diagnosis and therapeutic targets. Using RNA‑sequencing (seq), the present study investigated differentially expressed genes (DEGs) in five samples from five idiopathic adhesive capsulitis patients and two samples from two acromioclavicular dislocation patients, without idiopathic adhesive capsulitis. The DEGs were analyzed using the following tools: Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes pathways analysis and protein‑protein interaction analysis. A total of 188 DEGs were identified and it was observed that 150 of these were upregulated and 38 were downregulated. It was hypothesized that various nutrient associated proteins may be associated with idiopathic adhesive capsulitis. The Matrix metalloproteinase family of proteins (MMPs), may exhibit a key role in the formation of abnormal collagen cross‑links. Overall, the comprehensive and detailed information collected in the present study, regarding idiopathic adhesive capsulitis, may provide a foundation on which in‑depth follow‑up experiments may be based, aimed at identifying novel strategies for treatment of this disease.

Primary frozen shoulder (PFS) is a common condition of uncertain etiology that is characterized by shoulder pain and restriction of active and passive glenohumeral motions. The pathophysiology involves chronic inflammation and fibrosis of the joint capsule. Single nucleotide polymorphisms (SNPs) at IL-1β , MMP3 , TGF-β1 , and GDF5 have been associated with risk of a variety of inflammatory diseases; however, no studies have examined these SNPs with susceptibility to PFS. We investigated allele and genotype frequencies of rs1143627 at IL-1β , rs650108 at MMP-3 , rs1800469 at TGF-β1 , and rs143383 at GDF5 in 42 patients with PFS and 50 healthy controls in a Chinese Han population. Serum samples from both cohorts were evaluated to determine the expression levels of IL-1 β . We found that the IL-1β rs1143627 CC genotype was associated with a decreased risk of PFS compared to the TT genotype ( P = 0.022) and that serum IL-1 β was expressed at a significantly higher level in the PFS cohort compared to that found in the control group ( P < 0.001). Our findings indicated no evidence of an association between rs650108, rs1800469, or rs143383 and PFS. IL-1 β is associated with susceptibility to PFS and may have a role in its pathogenesis in a Chinese Han population.

Objectives: We evaluated mRNA expression levels of genes that encode TGF-β1; the TGF-β1 receptor; the collagen-modifying enzymes LOX, PLOD1, and PLOD2; and the extracellular matrix proteins COMP, FN1, TNC and TNXB in synovial/capsule specimens from patients with idiopathic adhesive capsulitis. Possible associations between the measured mRNA levels and clinical parameters were also investigated., Methods: We obtained glenohumeral joint synovium/capsule specimens from 9 patients with idiopathic adhesive capsulitis who had not shown improvement in symptoms after 5 months of physiotherapy. Adhesive capsulitis was confirmed in all patients by magnetic resonance imaging. We also obtained specimens from 8 control patients who had underwent surgery for acute acromioclavicular joint dislocation and who had radiological indication of glenohumeral capsule alteration based on arthroscopic evaluation. mRNA expression in the synovium/capsule specimens was analyzed by quantitative reverse transcription PCR. The B2M and HPRT1 genes were used as references to normalize target gene expression in the shoulder tissue samples., Results: The synovium/capsule samples from the patients with adhesive capsulitis had significantly higher TNC and FN1 expression than those from the controls. Additionally, symptom duration directly correlated with expression of TGFβ1 receptor I., Conclusion: Elevated levels of TNC and FN1 expression may be a marker of capsule injury. Upregulation of TGFβ1 receptor I seems to be dependent on symptom duration; therefore, TGFβ signaling may be involved in adhesive capsulitis. As such, TNC, FN1 and TGFβ1 receptor I may also play roles in adhesive capsulitis by contributing to capsule inflammation and fibrosis.

Genetic factors may play an important role in frozen shoulder etiology, which may involve matrix metalloproteinase-3 (MMP3) gene polymorphisms. In this study, we examined single nucleotide polymorphisms in MMP3 for their association with frozen shoulder susceptibility in a Chinese Han population. The rs591058, rs650108, and rs679620 polymorphisms in the MMP3 gene were genotyped in 112 subjects diagnosed as having frozen shoulder and in 143 healthy controls. rs650108 was found to be significantly associated with an increased risk of frozen shoulder. For other single nucleotide polymorphisms, no statistically significant associations with frozen shoulder were found. In conclusion, our data demonstrated that the MMP3 rs650108 variant was significantly associated with increased frozen shoulder susceptibility in a Chinese Han population.

Background: Frozen shoulder is a common disorder that leads to substantial functional loss for patients by impairing activities of daily living. It also adversely affects patients and society by impairing the ability to work. Its pathogenesis is not fully understood. The aim of the present study was to perform a systematic review and meta-analysis to assess the evidence suggesting a genetic link to frozen shoulder., Methods: A literature search of MEDLINE, EMBASE, and CINAHL databases using relevant keywords revealed 5506 studies. After appropriate screening of titles, abstracts, and full studies, seven studies were analyzed., Results: Three studies investigated rates of frozen shoulder among relatives. One study (n = 1828 twin pairs) showed an 11.6% prevalence in twin pairs and demonstrated a heritability of 42% for frozen shoulder after adjusting for age. A second study (n = 273) showed that 20% of patients with frozen shoulder had a positive family history involving a first-degree relative. The relative risk of frozen shoulder was 4:1 when all patients with frozen shoulder were compared with a control population. A third study (n = 87) showed that 29% of patients with frozen shoulder had a first-degree relative with frozen shoulder. Two studies evaluated racial predilection for frozen shoulder. One study (n = 50) reported a substantially higher number of white patients (76%) with frozen shoulder than black patients (24%). A second study (n = 87) showed that being born or having parents or grandparents born in the British Isles were risk factors for frozen shoulder. Four immunological studies investigated human leukocyte antigen (HLA)-B27 as a risk factor for frozen shoulder. Meta-analysis of two of these studies with clearly defined controls showed significantly higher rates of HLA-B27 positivity in patients with frozen shoulder as compared with controls (p < 0.001)., Conclusion: The limited evidence points toward a genetic link to frozen shoulder. We used family history and racial predilection as markers for genetic association, both of which indicated the presence of a genetic predisposition to frozen shoulder. However, as there is a lack of unbiased genetic approaches, there is an opportunity for genome-wide association studies to address definitively the molecular genetics of frozen shoulder. Such studies may eventually lead to a better understanding of the pathogenesis of frozen shoulder and the development of novel therapeutic interventions., Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Purpose: Frozen Shoulder Syndrome is a fibrosis of the shoulder joint capsule that is clinically associated with Dupuytren's disease, a fibrosis of the palmar fascia. Little is known about any commonalities in the pathophysiology of these connective tissue fibroses. β-catenin, a protein that transactivates gene expression, and levels of IGF2 mRNA, encoding insulin-like growth factor-II, are elevated in Dupuytren's disease. The aim of this study was to determine if correlating changes in β-catenin levels and IGF2 expression are evident in Frozen Shoulder Syndrome., Methods: Tissue from patients with Frozen Shoulder Syndrome and rotator cuff tear were obtained during shoulder arthroscopies. Total protein extracts were prepared from tissue aliquots and β-catenin immunoreactivity was assessed by Western immunoblotting. In parallel, primary fibroblasts were derived from these tissues and assessed for IGF2 expression by quantitative PCR., Results: β-catenin levels were significantly increased in Frozen Shoulder Syndrome relative to rotator cuff tear when assessed by Western immunoblotting analyses. IGF2 mRNA levels were significantly increased in primary fibroblasts derived from frozen shoulder syndrome tissues relative to fibroblasts derived from rotator cuff tissues., Conclusions: As in Dupuytren's disease, β-catenin levels and IGF2 expression are elevated in Frozen Shoulder Syndrome. These findings support the hypothesis that these connective tissue fibroses share a common pathophysiology.

Purpose: The purpose of this study was to evaluate at the mRNA level a subset of extracellular matrix molecules relevant during healing and remodeling of rotator cuff tears., Type of Study: Controlled laboratory study., Methods: Bursal and rotator cuff tissue from the margin of the rotator cuff tear were harvested from 10 patients (mean age, 57.5 +/- 7.3 years) undergoing surgical repair of full-thickness rotator cuff tears. There were six male and four female patients with a mean duration of symptoms of 14.6 months (range, 2 to 60 months). The mean tear size was 4.4 cm. In addition, tissue was obtained from 6 cadaveric specimens with no gross evidence of rotator cuff tearing. Reverse transcription polymerase chain reaction (RT-PCR) was performed for type I, II, and III collagen, biglycan, decorin, and aggrecan, and normalized to the housekeeping gene GAPDH., Results: RT-PCR showed that both the bursa and rotator cuff margin had increased mRNA levels for type I and type III collagen in patients with full-thickness rotator cuff tears when compared with normal cadaveric controls. In addition, there was a significant decrease in decorin mRNA levels and an increase in aggrecan mRNA levels in the rotator cuff margin of torn rotator cuff tendons when compared with normal cadaveric controls., Conclusions: These results suggest that both the bursa and rotator cuff margin of patients with rotator cuff tears are actively remodeling after injury and that both tissues may potentially contribute to the healing process following repair., Clinical Relevance: These findings may help clinicians determine what aspects of the repair process can be manipulated to affect optimal ruptured tendon repair.

Little information exists on the molecular and biochemical pathophysiology of subacromial bursitis and rotator cuff disease. We investigated the pattern of expression of cytokines (interleukin [IL]-1beta, IL-1, IL-6, tumor necrosis factor [TNF] alpha, small inducible cytokines), metalloproteases, and cyclooxygenases in the subacromial bursa in patients with rotator cuff disease. Subacromial bursa specimens were prepared for molecular and biochemical analysis in patients undergoing shoulder surgery following an institutional review board-approved protocol. Specimens were analyzed for the presence of cytokines, metalloproteases, and cyclooxygenases by use of microarray for gene expression and immunohistocytochemistry. Microarray analysis for gene expression and immunohistochemistry demonstrated that the expression of several cytokine genes (TNF, IL-1alpha, IL-1beta, and IL-6) was increased in patients with subacromial bursitis compared with control specimens. Furthermore, the expression of metalloproteases (MMP-1 and MMP-9) and cyclooxygenases (COX-1 and COX-2) in the bursitis group was found to be increased as compared with controls. Although further investigation is required, these studies suggest that inflammation of the subacromial bursa does occur in patients with rotator cuff disease. These findings support the role of anti-inflammatory agents in the treatment of subacromial impingement and emphasize the importance of subacromial bursectomy to reduce inflammation in rotator cuff disease.

Introduction: Primary hypoparathyroidism and adhesive capsulitis of the shoulder in the same patient does not seem to have been reported previously. We report two cases in first-degree relatives., Patients: Case 1: In 1999, a 41-year-old woman experienced seizures simulating epilepsy. She had been treated 5 years earlier for idiopathic adhesive capsulitis of both shoulders. Computed tomography of the brain showed calcifications in the basal ganglia meeting criteria for Fahr's disease, and incipient bilateral cataract was found. A diagnosis of idiopathic primary hypoparathyroidism was given. After 1 month of calcium and vitamin D supplementation, improvements were noted in the clinical symptoms, laboratory test, and electroencephalogram. Case 2: The 70-year-old father of case 1, who had an unremarkable medical history, had been receiving treatment for about 2 years for adhesive capsulitis of the left shoulder. Routine laboratory tests disclosed idiopathic primary hypoparathyroidism. The outcome was favorable with calcium and vitamin D supplementation., Conclusion: Our cases suggest that there may be a common immunological or genetic basis for primary hypoparathyroidism and adhesive capsulitis. Alternatively, adhesive capsulitis may be a manifestation of hypoparathyroidism. Although genetic factors involved in primary hypoparathyroidism have been elucidated, the pathophysiology of the disease remains unclear. Finally, a chance association remains possible., (Copyright 2003 Elsevier SAS)

Objectives: To estimate the heritability of frozen shoulder (FS) and tennis elbow (TE) and to examine the two disorders for possible genetic or environmental associations., Methods: Self-reporting questionnaire data on risk factors for, and a physician diagnosis of, FS or TE were obtained from 865 monozygotic (MZ) and 963 dizygotic (DZ) unselected female twin pairs aged between 20 and 76 yr registered with the St Thomas' UK Adult Twin Registry. The heritability of each disorder was estimated in a classic twin study. The association between FS and TE was then explored by log-linear modelling comparing MZ with DZ individuals and twin pairs for the presence of both disorders., Results: The prevalence of FS and TE were 11.6 and 16.7%, respectively. A heritability of 42% was estimated for FS and 40% for TE after adjusting for age. There was no confounding by environmental risk factors. Log-linear modelling demonstrated FS and TE, independently, to be associated within members of a twin pair and confirmed a stronger association in MZ than DZ pairs. In addition the two disorders occurred together 2-3 times more frequently in individuals than would be expected by chance. However, there was no association between FS and TE across members of a twin pair, implying no evidence for a shared genetic component to the two disorders., Conclusions: Genetic factors are implicated in the aetiology of both frozen shoulder and tennis elbow but are independent of each other. The two disorders occur together 2-3 times more frequently than by chance in individuals. However, the association is most likely mediated by individual-specific environmental factors common to the two conditions and not by a common genetic susceptibility.