Mast cells exert pro-inflammatory effects of relevance to the pathophyisology of tendinopathy

Abstract

IntroductionWe have previously found an increased mast cell density in tendon biopsies from patients with patellar tendinopathy compared to controls. This study examined the influence of mast cells on basic tenocyte functions, including production of the inflammatory mediator prostaglandin E2 (PGE2), extracellular matrix remodeling and matrix metalloproteinase (MMP) gene transcription, and collagen synthesis.MethodsPrimary human tenocytes were stimulated with an established human mast cell line (HMC-1). Extracellular matrix remodeling was studied by culturing tenocytes in a three-dimensional collagen lattice. Survival/proliferation was assessed with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay. Levels of mRNA for COX-2, COL1A1, MMP1, and MMP7 were determined by quantitative real-time polymerase chain reaction (qPCR). Cox-2 protein level was assessed by Western blot analysis and type I procollagen was detected by immunofluorescent staining. PGE2 levels were determined using an enzyme-linked immunosorbent assay (ELISA).ResultsMast cells stimulated tenocytes to produce increased levels of COX-2 and the pro-inflammatory mediator PGE2, which in turn decreased COL1A1 mRNA expression. Additionally, mast cells reduced the type I procollagen protein levels produced by tenocytes. Transforming growth factor beta 1 (TGF-β1) was responsible for the induction of Cox-2 and PGE2 by tenocytes. Mast cells increased MMP1 and MMP7 transcription and increased the contraction of a three-dimensional collagen lattice by tenocytes, a phenomenon which was blocked by a pan-MMP inhibitor (Batimastat).ConclusionOur data demonstrate that mast cell-derived PGE2 reduces collagen synthesis and enhances expression and activities of MMPs in human tenocytes.

Are inflammatory cells increased in painful human tendinopathy? A systematic review

“…For example, it has been shown that mast cells exert proinflammatory effects on human tendon-derived cells in vitro . 46 Macrophage depletion has been shown to increase the ultimate tensile strength of healing mice Achilles tendons 47. Changes in macrophage phenotype and epithelial-to-mesenchymal transition genes have been noted following Achilles tenotomy and during repair 29.…”

Tendon extracellular matrix damage, degradation and inflammation in response to in vitro overload exercise

“…We choose to study IL‐6 as this inflammatory mediator has previously been linked to tendinopathy24 and COX‐2 as increased levels of COX‐2 have been shown in patellar tendinopathy,26, 27 loaded human tendon cells39 and injured tendons 40. Other markers of inflammation such as IL‐1 were not included in this study but have previously been implicated in tendinopathic tendons41, 42 or bursa of the shoulder 25.…”

“…Both the inflammatory markers selected, IL‐624, 25 and COX‐226, 27 have previously been shown to be upregulated in tendinopathy. MMPs 1 and 13 were selected as they are known to be active against fibrillar collagens, including the predominant collagen type I 1, 28, 29, 30.…”

Teriparatide Treatment Improves Bone Defect Healing Via Anabolic Effects on New Bone Formation and Non-Anabolic Effects on Inhibition of Mast Cells in a Murine Cranial Window Model

“…However, mast cells are also known to be central mediators of chronic fibrosis via degranulation and release of fibroblast growth factors (FGF), tumor growth factors (TGF), platelet derived growth factor (PDGF), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), and other factors that promote progressive sclerosis, and several other chronic fibrotic conditions (ie, pulmonary fibrosis, renal fibrosis, and scleroderma). Moreover, the recent studies identifying mast cells as potential mediators in musculoskeletal diseases (ie, tendinopathy, inflammatory myopathy), via their deregulation and TGFβ1‐induced fibrosis, suggests a role for mast cells in failed tissue healing …”