BACKGROUND: Low levels of vitamin D have been associated with several autoimmune diseases. A growing body of evidence supports the association of vitamin D with skeletal muscle damage, regeneration, and energy and lipid metabolism. The aim was to analyse vitamin D and its receptor (VDR) in the muscle tissue of patients with idiopathic inflammatory myopathies (IIM) and to relate them to clinical parameters and muscle lipid and energy metabolism. METHODS: Forty-six patients with IIM and 67 healthy controls (HC) were included in the study. 27 IIM patients participated in a 24-week exercise intervention. Muscle biopsies were obtained from 7 IIM patients before/after training, 13 non-exercising IIM controls, and 21 HC. Circulating concentrations of 25(OH)D and 1,25(OH)D were measured. Gene expression of VDR and CYP27B1, the enzyme converting 25(OH)D to hormonally active 1,25(OH)D, was determined by qPCR in muscle tissue and primary muscle cells. Lipid oxidative metabolism was assessed in muscle tissue (mRNA, qPCR) and primary muscle cells (radioactive assays). RESULTS: Lower levels of active 1,25(OH)D were observed in IIM patients compared with HC (mean ± SD: 125.0 ± 45.4 vs. 164.7 ± 49.2 pmol/L; p < 0.0001). 25(OH)D was associated with CRP (r = -0.316, p = 0.037), MITAX (r = -0.311, p = 0.040) and HAQ (r = -0.390, p = 0.009) in IIM. After 24 weeks of training, active 1,25(OH)D was associated with MMT8 (r = 0.866, p < 0.0001), FI-2 (r = 0.608, p = 0.013) and HAQ (r = -0.537, p = 0.032). Gene expression of both VDR and CYP27B1 in primary muscle cells decreased after training (p = 0.031 and p = 0.078, respectively). Associations of VDR mRNA in muscle tissue with MMT-8 (IIM: r = -0.559, p = 0.013), serum CK (HC: r = 0.484, p = 0.031), myoglobin (IIM: r = 0.510, p = 0.026) and myostatin (IIM: r = -0.519, p = 0.023) were observed. The expression of VDR in differentiated muscle cells correlated negatively with the complete oxidation of palmitic acid (r = -0.532, p = 0.028). Muscle mRNA of carnitine palmitoyl transferase 1 (CPT1) (downregulated in IIM, p = 0.001) correlated positively with serum 1,25(OH) vitamin D (r = 0.410, p = 0.042). CONCLUSION: Reduced biologically active vitamin D in circulation suggests its impaired metabolism in IIM. Serum vitamin D levels and gene expression of its receptor and activating enzyme in muscle tissue were modified by regular exercise and associated with disease manifestations, physical fitness, and muscle lipid metabolism of IIM patients.

• Keywords
• Lipid metabolism, Mitochondria, Muscle, Myositis, Physical activity, Vitamin D,
• MeSH
• Exercise physiology   MeSH
• Adult MeSH
• Muscle, Skeletal * metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lipid Metabolism * physiology   MeSH
• Myositis * metabolism   MeSH
• Receptors, Calcitriol * metabolism   genetics   MeSH
• Aged MeSH
• Physical Fitness * physiology   MeSH
• Vitamin D * metabolism   blood   analogs & derivatives   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 25-Hydroxyvitamin D3 1-alpha-Hydroxylase MeSH
• CYP27B1 protein, human MeSH Browser
• Receptors, Calcitriol * MeSH
• VDR protein, human MeSH Browser
• Vitamin D * MeSH

OBJECTIVES: Our previous studies have demonstrated that the Damage Associated Molecular Pattern (DAMP) protein, S100A4, is overexpressed in the involved skin and peripheral blood of patients with SSc. It is associated with skin and lung involvement, and disease activity. By contrast, lack of S100A4 prevented the development of experimental dermal fibrosis. Herein we aimed to evaluate the effect of murine anti-S100A4 mAb 6B12 in the treatment of preestablished experimental dermal fibrosis. METHODS: The effects of 6B12 were assessed at therapeutic dosages in a modified bleomycin-induced dermal fibrosis mouse model by evaluating fibrotic (dermal thickness, proliferation of myofibroblasts, hydroxyproline content, phosphorylated Smad3-positive cell count) and inflammatory (leukocytes infiltrating the lesional skin, systemic levels of selected cytokines and chemokines) outcomes, and transcriptional profiling (RNA sequencing). RESULTS: Treatment with 7.5 mg/kg 6B12 attenuated and might even reduce pre-existing dermal fibrosis induced by bleomycin as evidenced by reduction in dermal thickness, myofibroblast count and collagen content. These antifibrotic effects were mediated by the downregulation of TGF-β/Smad signalling and partially by reducing the number of leukocytes infiltrating the lesional skin and decrease in the systemic levels of IL-1α, eotaxin, CCL2 and CCL5. Moreover, transcriptional profiling demonstrated that 7.5 mg/kg 6B12 also modulated several profibrotic and proinflammatory processes relevant to the pathogenesis of SSc. CONCLUSION: Targeting S100A4 by the 6B12 mAb demonstrated potent antifibrotic and anti-inflammatory effects on bleomycin-induced dermal fibrosis and provided further evidence for the vital role of S100A4 in the pathophysiology of SSc.

• Keywords
• 6B12, S100A4, SSc, established dermal fibrosis, monoclonal antibody, treatment,
• MeSH
• Alarmins * MeSH
• Bleomycin toxicity   MeSH
• Fibrosis MeSH
• Skin * pathology   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Antibodies, Monoclonal pharmacology   MeSH
• Mice MeSH
• S100 Calcium-Binding Protein A4 genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Alarmins * MeSH
• Bleomycin MeSH
• Antibodies, Monoclonal MeSH
• S100 Calcium-Binding Protein A4 MeSH
• S100A4 protein, human MeSH Browser

This mini-review aims to introduce the association between Secretory clusterin/apolipoprotein J (sCLU) and diverse musculoskeletal diseases. A comprehensive review of the literature was performed to identify basic science and clinical studies, which implied the therapeutic and prognostic role of sCLU in diverse musculoskeletal diseases. sCLU is a multifunctional glycoprotein that is ubiquitously expressed in various tissues and is implicated in many pathophysiological processes. Dysregulated expression of sCLU had been reported to be assocaited with proliferative or apoptotic molecular processes and inflammatory responses, which participated in many pathophysiological processes such as degenerative musculoskeletal diseases including ischemic osteonecrosis, osteoarthritis (OA) and degenerative cervical myelopathy (spinal cord injury), neoplastic musculoskeletal diseases, inflammatory and autoimmune musculoskeletal diseases including Rheumatoid arthritis (RA), joint damage induced by Brucella abortus, Sjogren's syndrome, idiopathic inflammatory myopathies, muscle glucose metabolism, insulin sensitivity and traumatic musculoskeletal diseases. Recent findings of sCLU in these musculoskeletal diseases provides insights on the therapeutic and prognostic role of sCLU in these musculoskeletal diseases. sCLU may serve as a promising therapeutic target for ischemic osteonecrosis, OA and spinal cord injury as well as a potential prognostic biomarker for OA and RA. Moreover, sCLU could act as a prognostic biomarker for osteosarcoma (OS) and a promising therapeutic target for OS resistance. Although many studies support the potential therapeutic and prognostic role of sCLU in some inflammatory and autoimmune-mediated musculoskeletal diseases, more future researches are needed to explore the molecular pathogenic mechanism mediated by sCLU implied in these musculoskeletal diseases.

• MeSH
• Biomarkers metabolism   MeSH
• Clusterin metabolism   MeSH
• Humans MeSH
• Musculoskeletal Diseases * diagnosis   therapy   MeSH
• Cell Line, Tumor MeSH
• Osteonecrosis * MeSH
• Spinal Cord Injuries * MeSH
• Prognosis MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Biomarkers MeSH
• Clusterin MeSH

Our previous study demonstrated that heat shock protein 90 (Hsp90) is overexpressed in the involved skin of patients with systemic sclerosis (SSc) and in experimental dermal fibrosis. Pharmacological inhibition of Hsp90 prevented the stimulatory effects of transforming growth factor-beta on collagen synthesis and the development of dermal fibrosis in three preclinical models of SSc. In the next step of the preclinical analysis, herein, we aimed to evaluate the efficacy of an Hsp90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), in the treatment of established experimental dermal fibrosis induced by bleomycin. Treatment with 17-DMAG demonstrated potent antifibrotic and anti-inflammatory properties: it decreased dermal thickening, collagen content, myofibroblast count, expression of transforming growth factor beta receptors, and pSmad3-positive cell counts, as well as leukocyte infiltration and systemic levels of crucial cytokines/chemokines involved in the pathogenesis of SSc, compared to vehicle-treated mice. 17-DMAG effectively prevented further progression and may induce regression of established bleomycin-induced dermal fibrosis to an extent comparable to nintedanib. These findings provide further evidence of the vital role of Hsp90 in the pathophysiology of SSc and characterize it as a potential target for the treatment of fibrosis with translational implications due to the availability of several Hsp90 inhibitors in clinical trials for other indications.

• Keywords
• established dermal fibrosis, heat shock protein 90, systemic sclerosis, treatment,
• Publication type
• Journal Article MeSH