S100A4-neutralizing monoclonal antibody 6B12 counteracts the established experimental skin fibrosis induced by bleomycin.

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-ß/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.

Hsp90 as a Myokine: Its Association with Systemic Inflammation after Exercise Interventions in Patients with Myositis and Healthy Subjects.

Compelling evidence supports the health benefits of physical exercise on the immune system, possibly through the molecules secreted by the skeletal muscles known as myokines. Herein, we assessed the impact of exercise interventions on plasma Heat shock protein 90 (Hsp90) levels in 27 patients with idiopathic inflammatory myopathies (IIM) compared with 23 IIM patients treated with standard-of-care immunosuppressive therapy only, and in 18 healthy subjects undergoing strenuous eccentric exercise, and their associations with the traditional serum markers of muscle damage and inflammation. In contrast to IIM patients treated with pharmacotherapy only, in whom we demonstrated a significant decrease in Hsp90 over 24 weeks, the 24-week exercise program resulted in a stabilization of Hsp90 levels. These changes in Hsp90 levels were associated with changes in several inflammatory cytokines/chemokines involved in the pathogenesis of IIM or muscle regeneration in general. Strenuous eccentric exercise in healthy volunteers induced a brief increase in Hsp90 levels with a subsequent return to baseline levels at 14 days after the exercise, with less pronounced correlations to systemic inflammation. In this study, we identified Hsp90 as a potential myokine and mediator for exercise-induced immune response and as a potential biomarker predicting improvement after physiotherapy in muscle endurance in IIM.

Non-coding RNAs in diseases with a focus on osteoarthritis.

Osteoarthritis (OA) is a frequent musculoskeletal disorder affecting millions of people worldwide. Despite advances in understanding the pathogenesis of OA, prognostic biomarkers or effective targeted treatment are not currently available. Research on epigenetic factors has yielded some new insights as new technologies for their detection continue to emerge. In this context, non-coding RNAs, including microRNAs, long non-coding RNAs, circular RNAs, piwi-interacting RNAs, and small nucleolar RNAs, regulate intracellular signaling pathways and biological processes that have a crucial role in the development of several diseases. In this review, we present current knowledge on the role of epigenetic factors with a focus on non-coding RNAs in the development, prediction and treatment of OA. This article is categorized under: RNA in Disease and Development > RNA in Disease.

Menopausal Transition: Prospective Study of Estrogen Status, Circulating MicroRNAs, and Biomarkers of Bone Metabolism.

Objective: Osteoporosis is associated with an impaired balance between bone resorption and formation, which in turn leads to bone loss and fractures. Many recent studies have underlined the regulatory role of microRNAs (miRNAs) in bone remodeling processes and their potential as biomarkers of osteoporosis. The purpose of this study was to prospectively examine the association of circulating miRNAs and bone biomarkers with estrogen status in women before and after oophorectomy, as well as in oophorectomized women on estrogen therapy. Methods: In this prospective study, we included 11 women before oophorectomy and hysterectomy and at 201 ± 24 days after the surgery. Another 11 women were evaluated 508 ± 127 days after oophorectomy and hysterectomy and after an additional 203 ± 71 days of estradiol treatment. Serum miRNAs were profiled by sequencing. Estrogen status and biomarkers of bone metabolism were quantified. Bone mineral density was assessed in the lumbar spine. Results: Our analysis revealed 17 miRNAs associated with estrogen levels. Of those miRNAs that were upregulated with estrogen deficiency and downregulated after estrogen therapy, miR-422a correlated with serum beta-carboxy-terminal type I collagen crosslinks (ß-CTX) and procollagen 1 N-terminal propeptide (P1NP); and miR-1278 correlated with serum ß-CTX, P1NP, osteocalcin, sclerostin, and Dickkopf-1(Dkk1). In contrast, we found an inverse association of miR-24-1-5p with estrogen status and a negative correlation with serum ß-CTX, P1NP, osteoprotegerin, and sclerostin levels. Conclusion: The reported miRNAs associated with estrogen status and bone metabolism could be potential biomarkers of bone pathophysiology and would facilitate studies on the prevention of postmenopausal osteoporosis. Our findings require validation in an extended cohort.