Background Tenogenesis and tendon homeostasis are guided by genes encoding for the structural molecules of tendon fibres. Small interfering RNAs (siRNAs), acting on gene regulation, can therefore participate in the process of tendon healing. Sources of data A systematic search of different databases to October 2020 identified 17 suitable studies. Areas of agreement SiRNAs can be useful to study reparative processes of tendons and identify possible therapeutic targets in tendon healing. Areas of controversy Many genes and growth factors involved in the processes of tendinopathy and tendon healing can be regulated by siRNAs. It is however unclear which gene silencing determines the expected effect. Growing points Gene dysregulation of growth factors and tendon structural proteins can be influenced by siRNA. Areas timely for developing research It is not clear whether there is a direct action of the siRNAs that can be used to facilitate the repair processes of tendons.

Small interfering RNAs in tendon homeostasis.

Background Rotator cuff tendinopathy (RCT) is a common musculoskeletal disorder in the shoulder, whose underlying mechanism is unknown. Long non-coding RNAs (lncRNAs) are involved in the development of various diseases, but little is known about their potential roles in RCT. Methods In this study, we profiled lncRNAs and mRNAs involved in RCT in comparison with the normal tendon (NT) by RNA sequencing (RNA-Seq), to identify potential therapeutic targets. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) pathway, competing endogenous RNA (ceRNA), and co-expression network construction were used to identify the potential functions of these RNAs. Three lncRNAs and three mRNAs were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results In total, 419 lncRNAs and 1,541 mRNAs were differentially expressed between the RCT and NT groups with a fold change of >2 and P of <0.01. The GO and KEGG pathway analyses showed that the differentially expressed mRNAs were mainly enriched in complement activation and involved in the citrate cycle. The ceRNA network showed the interaction of differentially expressed RNAs, comprising 139 lncRNAs, 126 mRNAs, and 35 miRNAs. NONHSAT209114.1, ENST00000577806, NONHSAT168464.1, PLK2, TMEM214, and IGF2 were validated by PCR. We constructed a co-expressed network of these validated RNAs. Conclusions We preliminarily analyzed the profile of lncRNAs and mRNAs in RCT. The bioinformatic analysis revealed several potential therapeutic targets for RCT.

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Conjoint analysis of lncRNA and mRNA expression in rotator cuff tendinopathy

Sustained oxidative stress and inflammation have been reported as the major factors responsible for the failure of tendon healing during rotator cuff tears (RCTs) and rotator cuff disease (RCD). Although, their therapeutic management remains still challenging. Carbonic anhydrases (CAs) are involved in many pathological conditions, and the overexpression of both CA9 and 12 in inflamed joints has been recently reported. Consequently, a selective CA9/12 inhibition could be a feasible strategy for improving tendon recovery after injury. In addition, since carbon monoxide (CO) has been proven to have an important role in modulating inflammation, CO releasing molecules (CORMs) can be also potentially suitable compounds. The present study aims at evaluating five newly synthesized dual-mode acting CA inhibitors (CAIs)-CORMs compounds, belonging to two chemical scaffolds, on tendon-derived human primary cells under H2O2 stimulation in comparison with Meloxicam. Our results show that compounds 2 and 7 are the most promising of the series in counteracting oxidative stress-induced cytotoxicity and display a better profile in terms of enhanced viability, decreased LDH release, and augmented tenocyte proliferation compared to Meloxicam. Moreover, compound 7, as a potent superoxide scavenger, exerts its action inhibiting NF-ĸB translocation and downregulating iNOS, whereas compound 2 is more effective in increasing collagen I deposition. Taken together, our data highlight a potential role of CA in RCTs and RCD and the prospective effectiveness of compounds acting as CAI-CORM during inflammation.

https://www.mdpi.com/2227-9059/9/2/141/pdf

Dual Acting Carbon Monoxide Releasing Molecules and Carbonic Anhydrase Inhibitors Differentially Modulate Inflammation in Human Tenocytes.

1 Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, Salerno, Italy 2 Department of Physical and Rehabilitation Medicine, Casa di Cura Policlinico San Marco, Venice, Italy 3 Department of Medicine and Surgery, University of Parma, Parma, Italy 4 Clinical Laboratory of Experimental Neurorehabilitation, I.R.C.C.S. Santa Lucia Foundation, Rome, Italy 5 Department of Emergency and Acceptance, Orthopaedics and Traumatology Unit, San Camillo-Forlanini Hospital, Rome, Italy 6 Physical and Rehabilitation Medicine, University of Rome Tor Vergata, Rome, Italy 7 Isokinetic Medical Group, FIFA Medical Centre of Excellence, Bologna, Italy 8 Biomedical Research Centre, Gruppo Forte, Salerno, Italy 9 Department of Surgery, Oncology and Gastroenterology DiSCOG, Orthopedic Clinic, University of Padova, Padova, Italy 10 Physical Medicine and Rehabilitation Unit, Sant’Andrea Hospital, “Sapienza” University of Rome, Rome, Italy 11 UOC Immunohematology and Transfusion Medicine Laboratories, Laboratory of Stem Cells, Spirito Santo Hospital, Pescara, Italy 12 Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopedic Institute, Bologna, Italy 13 Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy

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I.S.Mu.L.T. Reccomendations for Intra and Periarticular Injections during COVID19 Pandemic

Rotator cuff tears (RCTs) and rotator cuff disease (RCD) are important causes of disability in middle-aged individuals affected by nontraumatic shoulder dysfunctions. Our previous studies have demonstrated that four different hyaluronic acid preparations (HAPs), including Artrosulfur® hyaluronic acid (HA) (Alfakjn S.r.l., Garlasco, Italy), may exert a protective effect in human RCT-derived tendon cells undergoing oxidative stress damage. Recently, methylsulfonylmethane (MSM) (Barentz, Paderno Dugnano, Italy) has proven to have anti-inflammatory properties and to cause pain relief in patients affected by tendinopathies. This study aims at evaluating three preparations (Artrosulfur® HA, MSM, and Artrosulfur® MSM + HA) in the recovery from hydrogen peroxide-induced oxidative stress damage in human tenocyte. Cell proliferation, Lactate Dehydrogenase (LDH) release, and inducible nitric oxide synthases (iNOS) and prostaglandin E2 (PGE2) modulation were investigated. In parallel, expression of metalloproteinases 2 (MMP2) and 14 (MMP14) and collagen types I and III were also examined. Results demonstrate that Artrosulfur® MSM + HA improves cell escape from oxidative stress by decreasing cytotoxicity and by reducing iNOS and PGE2 secretion. Furthermore, it differentially modulates MMP2 and MMP14 levels and enhances collagen III expression after 24 h, proteins globally related to rapid acceleration of the extracellular matrix (ECM) remodelling and thus tendon healing. By improving the anti-cytotoxic effect of HA, the supplementation of MSM may represent a feasible strategy to ameliorate cuff tendinopathies.

https://www.mdpi.com/1422-0067/21/21/7956/pdf

Conjugation with Methylsulfonylmethane Improves Hyaluronic Acid Anti-Inflammatory Activity in a Hydrogen Peroxide-Exposed Tenocyte Culture In Vitro Model.

Background Rotator cuff tendinopathy is a common musculoskeletal ailment in sedentary and athletic individuals. Various mediators of inflammation have been detected in human tendons: they are thought to initiate or progress the course of tendinopathy. Sources of data An online search was conducted using AMED, CINAHL, Embase, The Cochrane Library, PEDro and Pubmed, using the terms tendinopathy, tendon, tendinitis, tendinosis, histology, histopathology, immunohistochemistry, immunohistochemical, rotator cuff and pain. Areas of agreement Histological examination of tendinopathic tendons shows degeneration of the collagen structure and infiltration of fat and vessels, together with increased expression of inflammatory cytokines, MMP-1, 2, 3, 9, 13, vascular endothelial growth factor and Hypoxia inducible factor (HIF). Areas of controversy Most of the studies about this topic exhibited limited validity because of lack of appropriately matched controls and no inclusion or exclusion criteria. The evidence associated with the histopathological analysis of the rotator cuff is limited. Growing points The histochemical and immunohistochemical features of rotator cuff tendinopathy are still unclear. A thorough understanding of the vascularity, innervation and biochemical mediators of pain could be used to target rotator cuff pathology, and possibly guide the therapy of painful rotator cuff disorders. Areas timely for developing research There is a need for a validated reproducible method of rotator cuff tendon biopsy evaluation. We require further studies with improved designs to effectively evaluate the histological and immunohistochemical features of rotator cuff tendinopathy.

Rajpreet Sahemey

Papers

Immunohistochemical features of rotator cuff tendinopathy.