Molecular mechanism of the influence of related genes expression in synovium tissue around shoulder joint of secondary frozen shoulder model rats on angiogenesis.

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.

Agomir-122-loaded nanoparticles coated with cell membrane of activated fibroblasts to treat frozen shoulder based on homologous targeting.

As a common musculoskeletal disorder, frozen shoulder is characterized by thickened joint capsule and limited range of motion, affecting 2-5% of the general population and more than 20% of patients with diabetes mellitus. Pathologically, joint capsule fibrosis resulting from fibroblast activation is the key event. The activated fibroblasts are proliferative and contractive, producing excessive collagen. Albeit high prevalence, effective anti-fibrosis modalities, especially fibroblast-targeting therapies, are still lacking. In this study, microRNA-122 was first identified from sequencing data as a potential therapeutic agent to antagonize fibroblast activation. Then, Agomir-122, an analog of microRNA-122, was loaded into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Agomir-122@NP), a carrier with excellent biocompatibility for the agent delivery. Moreover, relying on the homologous targeting effect, we coated Agomir-122@NP with the cell membrane derived from activated fibroblasts (Agomir-122@MNP), with an attempt to inhibit the proliferation, contraction, and collagen production of abnormally activated fibroblasts. After confirming the targeting effect of Agomir-122@MNP on activated fibroblasts in vitro, we proved that Agomir-122@MNP effectively curtailed fibroblasts activation, ameliorated joint capsule fibrosis, and restored range of motion in mouse models both prophylactically and therapeutically. Overall, an effective targeted delivery method was developed with promising translational value against frozen shoulder.

Frozen shoulder. An overview of pathology and biology with hopes to novel drug therapies.

Frozen shoulder (FS) is a common disorder characterized by spontaneous onset of shoulder pain accompanied by progressive loss of range-of-motions. The cause of FS is still unclear, and radical therapy has not been established. With the final aim of preventing or curing FS at an earlier stage, we reviewed the pathological and biological features of this disease. Many studies indicate that the main pathology of FS is inflammation initially and fibrosis later. There are inflammatory cytokines, immune cells, fibrotic growth factors, and type-III collagen in the synovium and the joint capsule. The immune cell landscape switches from the macrophages to T cells. Activated fibroblasts seem to regulate the inflammatory and fibrotic processes. The imbalance between matrix metalloproteinases and tissue inhibitors of metalloproteases might promote fibrosis. Additionally, advanced glycation end-products are noted in the FS synovium. Diabetes mellitus and hypothyroidism are closely related to the development of FS. In terms of nonsurgical treatment, oral or intra-articular glucocorticoids are the only drugs that provide early benefit. Some other anti-inflammatory or antifibrotic drugs may potentially control the FS, but have not been proven effective in the clinical setting. Future studies should be targeted to develop steroid-sparing agents that inhibit biological events in FS.

Increased Expression of Adipokines in Patients With Frozen Shoulder.

BACKGROUND: Adipokines represent a spectrum of bioactive molecules that could modulate fibroblastic and inflammatory processes. The role of adipokines in the pathogenesis of frozen shoulder (FS), a common musculoskeletal disorder characterized by chronic inflammation, remains obscure. PURPOSE: To evaluate whether adipokines contribute to the pathogenic mechanisms of FS and to evaluate any potential correlation of adipokines with patients' symptoms. STUDY DESIGN: Controlled laboratory study. METHODS: Shoulder capsule specimens were obtained from 10 patients with FS and 10 patients with shoulder instability (control group). The specimens were dyed using hematoxylin and eosin and immunohistochemically assessed with antibodies targeting adipokines, collagen I, collagen III, and tumor necrosis factor α. Immunoreactivity was graded from "no" to "strong" in a blinded manner. Reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) analysis was conducted. Before the surgery, patient-reported frequency of pain, severity of pain, stiffness, and shoulder range of motion were documented. RESULTS: In comparison with the control group, patients with FS had significantly greater pain frequency, pain severity, and stiffness and more limited shoulder range of motion (P < .001). Hematoxylin and eosin- and Masson trichrome-stained samples from the FS group displayed hypercellularity and increased collagen fibers. Immunohistochemistry and RT-qPCR analyses indicated that expression of adipokines was significantly increased in FS capsules compared with the control group. The expression of collagen I, collagen III, and tumor necrosis factor α was also increased in FS capsules. No significant correlation was noted between adipokine expression and patient-reported outcomes in the control group, whereas in patients with FS, adiponectin expression was correlated with pain frequency (r = 0.78; P = .01) and stiffness (r = 0.73; P = .02). Visfatin was also correlated with pain frequency (r = 0.70; P = .02). CONCLUSION/CLINICAL RELEVANCE: This study indicated a potential role for adipokines in the pathogenesis of FS and demonstrated a correlation between adipokine expression and patients' pain and stiffness.

MicroRNA-211-5p in extracellular vesicles derived from BMSCs facilitates the repair of rat frozen shoulder via regulating KDM2B/LACC1 axis.

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-ß, 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.

Fibrosis in frozen shoulder: Activation of IL-6 through PI3K-Akt signaling pathway in synovial fibroblast.

Fibrosis is the main cause of limited range of motion (ROM) of shoulder in patients with frozen shoulder (FS). Overexpression of Interleukin 6 (IL-6) has been correlated with pathogenesis of FS. However, the underlying mechanism remains largely unexplored. In the current study, we focused on isolating synovial fibroblasts of FS and determining the influence of IL-6 as well as PI3K-Akt signaling pathway on the fibrotic process of synovial fibroblasts in FS by using RNA Sequencing (RNA-seq) and other molecular biology techniques. Synovial fibroblasts of FS express more extra cellular matrix (ECM) than that of control. RNA-seq results and bioinformatic analysis indicate that PI3K-Akt signaling pathway play an important role in the fibrotic process of FS, and IL-6 is the most related gene among those related to this process. The expression levels of IL-6 / IL-6R in FS synovial fibroblasts and IL-6 in culture supernatant were both significantly increased. siRNA interference with the expression of IL-6 attenuates the fibrosis level of FS as well as phosphorylation level of Akt. The findings suggest that synovial fibroblasts are key effector cells of fibrosis of FS. Activation of PI3K-Akt pathway can promote fibrosis of synovial fibroblasts in FS. IL-6 is up-regulated in synovial fibroblasts of FS and promoted the FS fibrosis through PI3K-Akt signaling pathway.

Tetrandrine inhibits the occurrence and development of frozen shoulder by inhibiting inflammation, angiogenesis, and fibrosis.

BACKGROUND: Frozen shoulders (FS) is a major clinical concern, where chronic synovial inflammation, abnormal angiogenesis, and fibrosis represent the critical pathologies in the glenohumeral capsule. However, no pharmacotherapy has been introduced to treat this pathology. Tetrandrine (TET) has been proposed as a treatment for many diseases due to its strong anti-inflammatory, anti-angiogenic, and anti-fibrotic effects. PURPOSE: To study the anti-inflammatory, anti-angiogenic, and anti-fibrotic effects of TET on FS, and identify whether TET can prevent the development of FS in rats. STUDY DESIGN: A controlled laboratory study. METHODS: Forty-eight male Sprague-Dawley (SD) rats were randomly divided into control, TET, and FS groups. The TET group was intraperitoneally injected with TET every 2 days. TET and saline treatment were started on the day of FS surgery. After 8 weeks, the animals were sacrificed, and samples were collected for X-ray examination, glenohumeral range of motion (ROM) evaluation, histology and immunohistochemistry analysis, transmission electron microscopy (TEM) observation, and profibrogenic factors as well as proinflammatory cytokines measurements. RESULTS: No significant difference in shoulder ROM was observed between the TET and control groups, but a significant difference was noted between these groups and the FS group (P < 0.01). Immunohistochemical staining showed no abnormal angiogenesis or fibrosis in the TET group or the control group. However, significant angiogenesis, collagen remodeling, and fibrosis were observed in the FS group, and the expression and proportion of type I and type III collagen in the FS group were significantly higher than those in the TET group or the control group (P < 0.01). TEM observation showed that TET protected the ultrastructure of collagen fibrous reticular arrangement of the articular capsule and prevented the formation of scar-like fibrotic structures, which are unique to FS. The significantly increased expression of Smad7 and the suppressed expression of Smad 2 in the TET group compared with that of the FS group indicated that TET also significantly inhibited the TGF-ß1 intracellular signal pathway. The expression of profibrogenic factors and proinflammatory cytokines in the TET group and the control group was significantly lower than that in the TET group (P < 0.01). CONCLUSION: The results demonstrated that TET protected the normal reticular structure of the capsule during the freezing period and prevented the development of FS by inhibiting inflammation, angiogenesis, and fibrosis in a rat FS model. CLINICAL RELEVANCE: TET may be a safe and effective clinical medication for preventing and treating FS.

Collagens in primary frozen shoulder: expression of collagen mRNA isoforms in the different phases of the disease.

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-ß1, - ß2 and -ß3 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-ß1 and TGF-ß3 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.

Transcriptomic analysis of adhesive capsulitis of the shoulder.

Adhesive capsulitis (AC) is a disabling condition of the shoulder joint affecting 2 to 5% of the general population. Our understanding of the molecular mechanisms is limited. The present study aimed to determine potential biomarkers of AC through transcriptomic analysis. This multi-centre study investigated patients undergoing arthroscopic capsulotomy surgery for resistant AC compared to those undergoing arthroscopic stabilization surgery for glenohumeral instability (control). Tissue samples were harvested from the anterior capsule during surgery. Total RNA was extracted and RNA-sequencing-based transcriptomics were performed. A number of genes deemed differentially expressed in RNA-sequencing analysis were validated using real-time reverse transcription polymerase chain reaction (RT-PCR). Baseline characteristics of the AC group (n = 22) were; mean age 52.7 years (SD: 10.2), 73% female, and Oxford Shoulder Score 19.6 (SD: 8.0), compared with the control group (n = 26), average age 23.9 years (SD: 5.2), 15% female, and Oxford Shoulder Score 39.0 (SD: 7.4). Transcriptomic analysis with false discovery rate correction and log2 fold change cut-off of ±1.5 revealed 545 differentially expressed genes in AC relative to control. Bioinformatic analyses were carried out to identify biological processes and pathways enriched in this dataset. Real-time RT-PCR using two different normalization processes confirmed increased expression of matrix metallopeptidase 13 (MMP13) and platelet-derived growth factor subunit B (PDGFB), in patients with AC, while tumor necrosis factor α (TNFA) expression was reduced. These findings provide a comprehensive assessment of transcriptional changes associated with AC that give insights into the aetiology of the disease and provides a resource for molecular targets to better diagnose and treat this condition.

RAGE-dependent NF-kB inflammation processes in the capsule of frozen shoulders.

BACKGROUND: The etiology of frozen shoulder (FS) remains uncertain. Advanced glycation end-products (AGEs) cause the cross-linking and stabilization of collagen and are increased in FS. The purpose of this study was to elucidate the pathogenesis of FS by evaluating the receptor of AGE (RAGE)-dependent pathways. METHODS: Tissue samples of the coracohumeral ligament (CHL) and anterior inferior glenohumeral ligament (IGHL) were collected from 33 patients with FS, with severe stiffness, and 25 with rotator cuff tears (RCTs) as controls. Gene expression levels of RAGE, high-mobility group box 1 (HMGB1), Toll-like receptor 2 (TLR2), TLR4, nuclear factor-kappa B (NF-kB), and cytokines were evaluated using a quantitative real-time polymerase chain reaction. The immunoreactivities of carboxymethyllysine (CML), pentosidine, and RAGE were also evaluated. CML and pentosidine were further evaluated using high-performance liquid chromatography. RESULTS: Gene expression levels of RAGE, HMGB1, TLR2, TLR4, and NF-kB were significantly greater in the CHLs and IGHLs from the FS group than in those from the RCT group. Immunoreactivities of RAGE and CML were stronger in the CHLs and IGHLs from the FS group than in those from the RCT group. Pentosidine was weakly immunostained in the CHLs and IGHLs from the FS group. CML using high-performance liquid chromatography was significantly greater in the CHLs and IGHLs from the FS group than in those from the RCT group. CONCLUSIONS: AGEs and HMGB1 might play important roles in the pathogenesis of FS by binding to RAGE and activating NF-kB signaling pathways. Suppression of these pathways could be a treatment option for FS.

MicroRNA-29a Mitigates Subacromial Bursa Fibrosis in Rotator Cuff Lesion with Shoulder Stiffness.

Rotator cuff lesion with shoulder stiffness is a major cause of shoulder pain and motionlessness. Subacromial bursa fibrosis is a prominent pathological feature of the shoulder disorder. MicroRNA-29a (miR-29a) regulates fibrosis in various tissues; however, the miR-29a action to subacromial bursa fibrosis remains elusive. Here, we reveal that subacromial synovium in patients with rotator cuff tear with shoulder stiffness showed severe fibrosis, hypertrophy, and hyperangiogenesis histopathology along with significant increases in fibrotic matrices collagen (COL) 1A1, 3A1, and 4A1 and inflammatory cytokines, whereas miR-29a expression was downregulated. Supraspinatus and infraspinatus tenotomy-injured shoulders in transgenic mice overexpressing miR-29a showed mild swelling, vascularization, fibrosis, and regular gait profiles as compared to severe rotator cuff damage in wild-type mice. Treatment with miR-29a precursor compromised COL3A1 production and hypervascularization in injured shoulders. In vitro, gain of miR-29a function attenuated COL3A1 expression through binding to the 3'-untranslated region (3'-UTR) of COL3A1 in inflamed tenocytes, whereas silencing miR-29a increased the matrix expression. Taken together, miR-29a loss is correlated with subacromial bursa inflammation and fibrosis in rotator cuff tear with shoulder stiffness. miR-29a repressed subacromial bursa fibrosis through directly targeting COL3A1 mRNA, improving rotator cuff integrity and shoulder function. Collective analysis offers a new insight into the molecular mechanism underlying rotator cuff tear with shoulder stiffness. This study also highlights the remedial potential of miR-29a precursor for alleviating the shoulder disorder.

Role of matrix metalloproteinases 2 and 9 in the development of frozen shoulder: human data and experimental analysis in a rat contracture model.

BACKGROUND: Although frozen shoulder (FS) is a common shoulder disorder, its pathogenesis is not yet determined. The function of matrix metalloproteinases (MMPs) is related to extracellular matrix remodeling. The purposes of this study were to investigate the pattern of sequential expression of MMPs in a rat model of shoulder contracture and to compare the expression of MMPs in the joint capsule between patients with FS and a control group. METHODS: We obtained joint capsules from rats immobilized by molding plaster (a shoulder contracture model) at baseline, 3 days, 1 week, and 3 weeks (4 rats per time point; 16 rats in total). The expression of the inflammatory cytokine interleukin 6 (IL-6), MMP-2, and MMP-9 was examined by immunohistochemistry. We also obtained joint capsules from 21 patients with FS and 13 control patients with instability to quantify the expression levels of MMP-2 and MMP-9 by immunohistochemistry. RESULTS: In the rat model, IL-6 and MMP-9 tended to be overexpressed in the joint capsule at 3 days and 1 week and MMP-2 at 3 days, 1 week, and 3 weeks. MMP-2 and MMP-9 were significantly overexpressed in the joint capsules of the patients with FS compared with those of control patients. CONCLUSION: The results from both human and animal studies suggest the involvement of MMP-2 and MMP-9 in the development of FS. Animal study showed that the sequential expression of IL-6 and MMPs may be associated with fibrosis of the joint capsule.

Biological Aspect of Pathophysiology for Frozen Shoulder.

It is fairly well understood that frozen shoulder involves several stages, which reflect the series of process from capsular inflammation and fibrosis to spontaneous resolution of this fibrosis. However, the underlying pathophysiologic process remains poorly determined. For this reason, management of frozen shoulder remains controversial. Determining the pathophysiological processes of frozen shoulder is a pivotal milestone in the development of novel treatment for patients with frozen shoulder. This article reviews what is known to date about the biological pathophysiology of frozen shoulder. Although articles for the pathophysiology of frozen shoulder provide inconsistent and inconclusive results, they have suggested both inflammation and fibrosis mediated by cytokines, growth factors, matrix metalloproteinases, and immune cells. Proinflammatory cytokines and growth factors released from immune cells control the action of fibroblast and matrix remodeling is regulated by the matrix metalloproteinases and their inhibitors. To improve our understanding of the disease continuum, better characterizing the biology of these processes at clearly defined stages will be needed. Further basic studies that use standardized protocols are required to more narrowly identify the role of cytokines, growth factors, matrix metalloproteinases, and immune cells. The results of these studies will provide needed clarity into the control mechanism of the pathogenesis of frozen shoulder and help identify new therapeutic targets for its treatment.

Comparative proteome analysis of the capsule from patients with frozen shoulder.

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.

Alarmins in Frozen Shoulder: A Molecular Association Between Inflammation and Pain.

BACKGROUND: The pathophysiological mechanisms behind proliferation of fibroblasts and deposition of dense collagen matrix in idiopathic frozen shoulder remain unclear. Alarmins (also known as danger signals) are endogenous molecules that are released into the extracellular milieu after infection or tissue injury and that signal cell and tissue damage. PURPOSE: To investigate whether the presence of alarmins is higher in patients with idiopathic frozen shoulder than in control subjects. STUDY DESIGN: Controlled laboratory study. METHODS: Shoulder capsule samples were collected from 10 patients with idiopathic frozen shoulder and 10 patients with unstable shoulders (control). The samples were stained with hematoxylin and eosin (H&E) and analyzed by immunohistochemistry using antibodies against alarmin molecules including high-mobility group protein B1 (HMGB1), interleukin 33, S100A8, S100A9, and the peripheral nerve marker PGP9.5. Immunoreactivities were rated in a blinded fashion from "none" to "strong." Immunohistochemical distribution within the capsule was noted. Before surgery, patient-ranked pain frequency, severity, stiffness, and the range of passive shoulder motion were recorded and statistically analyzed. RESULTS: Compared with control patients, patients with frozen shoulder had greater frequency and severity of self-reported pain ( P = .02) and more restricted range of motion in all planes ( P < .05). H&E-stained capsular tissue from frozen shoulder showed fibroblastic hypercellularity and increased subsynovial vascularity. Immunoreactivity of alarmins was significantly stronger in frozen shoulder capsules compared with control capsules ( P < .05). Furthermore, the expression of the alarmin molecule HMGB1 significantly correlated ( r > 0.9, P < .05) with the severity of patient-reported pain. CONCLUSION: This study demonstrates a potential role for key molecular danger signals in frozen shoulder and suggests an association between the expression of danger molecules and the pain experienced by patients.

The influence of platelet rich plasma on synovial fluid volumes, protein concentrations, and severity of pain in patients with knee osteoarthritis.

Knee pain is commonly seen in orthopedic and rehabilitation outpatient clinical settings. Patients with knee osteoarthritis (OA) are often complicated with joint soreness, swelling, weakness, and pain. These complaints are often caused by the excessive amount of synovial fluid (SF) accumulated in the bursae around the knee joint. This study was aimed to evaluate the effectiveness of platelet rich plasma (PRP) in treating patients with minor to moderate knee osteoarthritis (OA) combined with supra-patellar bursitis using a proteomic approach and clinical evaluation tool. In this study, 24 elderly patients with minor to moderate knee OA combined with supra-patellar bursitis were recruited. Musculoskeletal ultrasound was used for accurate needle placement for the aspiration of SF followed by subsequent PRP injections. Three monthly PRP injections were performed to the affected knees for a total of 3months. Approximately after the 2nd PRP injection, significant decreases in SF total protein concentrations, volumes, and Lequesne index values were observed. SF proteins associated with chelation and anti-aging physiological functions such as matrilin, transthyretin, and complement 5 increased at least 2-fold in concentrations. Proteins associated with inflammation, such as apolipoprotein A-I, haptoglobin, immunoglobulin kappa chain, transferrin, and matrix metalloproteinase decreased at least 2-fold in concentrations. Therefore, at least two monthly PRP injections may be beneficial for treating patients with minor to moderate knee OA combined with supra-patellar bursitis.

The roles of Tenascin C and Fibronectin 1 in adhesive capsulitis: a pilot gene expression study.

OBJECTIVES: We evaluated mRNA expression levels of genes that encode TGF-ß1; the TGF-ß1 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 TGFß1 receptor I. CONCLUSION: Elevated levels of TNC and FN1 expression may be a marker of capsule injury. Upregulation of TGFß1 receptor I seems to be dependent on symptom duration; therefore, TGFß signaling may be involved in adhesive capsulitis. As such, TNC, FN1 and TGFß1 receptor I may also play roles in adhesive capsulitis by contributing to capsule inflammation and fibrosis.

The roles of Tenascin C and Fibronectin 1 in adhesive capsulitis: a pilot gene expression study

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.