Differential expression of alarmins—S100A9, IL-33, HMGB1 and HIF-1α in supraspinatus tendinopathy before and after treatment

Mosca, Michael J.; Carr, Andrew; Snelling, Sarah; Wheway, Kim; Watkins, Bridget; Dakin, Stephanie G.

doi:10.1136/bmjsem-2017-000225

Cited by 29 publications

(44 citation statements)

References 46 publications

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“…The tissue and cells derived from tendinopathic and ruptured Achilles tendons show evidence of chronic (non-resolving) inflammation (13). Additional clinical studies support this finding showing enhanced levels of HMGB1 in early stage supraspinatus tendinopathy tissues compared to normal tissues and late stage tendinopathy tissues (37, 38). Moreover, the in vitro study shows that recombinant HMGB1 induces significant inflammatory mediators such as IL-1β, IL-6, IL-33, CCL2, and CXCL-12 (37).…”

Section: Discussionsupporting

confidence: 64%

“…Moreover, the amplification of the PGE 2 biosynthesis pathway by HMGB1/IL-1β is suggested as an important pathogenic mechanism perpetuating inflammatory and destructive activities in rheumatoid arthritis (51). While it is currently unclear whether our findings will reflect the actual mechanisms of tendinopathy development and treatment in humans, recent studies demonstrated that HMGB1 is present in human tendinopathic tendons and regulates cellular inflammation and protein production in vitro (37, 38). This suggests that HMGB1 plays a similar role in the development of tendinopathy due to mechanical overloading.…”

Section: Discussionmentioning

confidence: 94%

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HMGB1 mediates the development of tendinopathy due to mechanical overloading

Zhao

Zhang

Nie

et al. 2019

Preprint

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15 Mechanical overloading is a major cause of tendinopathy, but the underlying pathogenesis of 16 tendinopathy is unclear. Here we report that high mobility group box1 (HMGB1) is released to 17 the tendon extracellular matrix and initiates an inflammatory cascade in response to mechanical 18 overloading in a mouse model. Moreover, administration of glycyrrhizin (GL), a naturally 19 occurring triterpene and a specific inhibitor of HMGB1, the tendon's inflammatory reactions.20 Also, while prolonged mechanical overloading in the form of long-term intensive treadmill 21 running induces Achilles tendinopathy in mice, administration of GL completely blocks the 22 tendinopathy development. Additionally, mechanical overloading of tendon cells in vitro induces 23 HMGB1 release to the extracellular milieu, thereby eliciting inflammatory and catabolic 24 responses as marked by increased production of prostaglandin E 2 (PGE 2 ) and matrix 25 metalloproteinase-3 (MMP-3) in tendon cells. Application of GL abolishes the cellular 26 inflammatory/catabolic responses. Collectively, these findings point to HMGB1 as a key 27 molecule that is responsible for the induction of tendinopathy due to mechanical overloading 28 placed on the tendon. 29 Keywords: Mechanical overloading, HMGB1, tendinopathy, tendon inflammation, tendon 30 degeneration, glycyrrhizin 31 32 Introduction 33 34Tendinopathy, a debilitating chronic tendon disorder, is manifested in clinical settings by 35 a combination of pain, swelling, compromised tendon structure, and rupture (1). Tendinopathy, 36 which involves tendon inflammation and degeneration, affects healthy individuals during their 37 active and productive years of life resulting in tremendous healthcare costs and economic impact 38 due to work-loss (2, 3). In particular, insertional tendinopathy, which is common in young 39 athletes, often occurs in the tendon proper proximal to the insertion into the heel bone and 40 accounts for about 20% of Achilles tendon disorders (4). It is well established that while normal 41 physiological loading is essential for tendon homeostasis, mechanical overloading induces the 42 development of tendinopathy, characterized by disorganized matrix, reduced numbers and 43 rounding of tendon cells, fibrocartilaginous change, and neovascularization (5, 6). A current 44 concept on the mechanisms of tendinopathy is that repetitive loading may lead to a 45 mechanobiological over-stimulation of tendon cells resulting in an imbalance between the 46 synthesis and breakdown of matrix proteins, especially collagen (7-9). The resulting mismatch is 47 a continuous loss of collagen in the tendon by repetitive loading with insufficient recovery time, 48 which initiates a catabolic degenerative response that leads to tendinopathy (6, 10). 50It is now recognized that inflammation is part of tendinopathy and could lead to tendon 51 degeneration that occurs at late stages of tendinopathy (11)(12)(13). Under excessive mechanical 52 loading, abnormal levels of proinflammatory mediators may be rel...

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 94%

HMGB1 mediates the development of tendinopathy due to mechanical overloading

Zhao

Zhang

Nie

et al. 2019

Preprint

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“…In keeping with previous studies, the predominant immune cell sub-types in tendon are monocytes and Tc cells (28). Similarly, immunostaining of diseased human Achilles samples found reduced levels of IL33 compared to healthy or treated patient samples and this was associated with CD68+ macrophages on immuno-flourescence (29). In our study, IL33 expression was predominantly found in clusters containing cells with endothelial gene markers and high surface CD31/ CD34, with little expression in CD68+ clusters or cells expressing collagen genes.…”

Section: Higher Levels Of Col4a1 Krt7 Postn Tagln Thbs1 Timp3 Isupporting

confidence: 90%

Identification of human tendon cell populations in healthy and diseased tissue using combined single cell transcriptomics and proteomics

Kendal

Layton

Al-Mossawi

et al. 2019

Preprint

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The long-term morbidity of tendon disease in an increasingly active and ageing population represents a growing area of unmet clinical need. Tendon disorders commonly affect the lower limb, ranging from isolated tendon rupture to degenerative joint deformity. In the absence of valid animal models of chronic tendinopathy, traditional methods to isolate and identify crucial sub types involved in disease are limited by the heterogeneity of tendon cells, by their relative paucity in tissue and by the density of the surrounding collagen matrix. To overcome this, we have used next generation CITE-sequencing to combine surface proteomics with in-depth, unbiased gene expression analysis of single cells derived ex vivo from healthy and diseased tendon.For the first time we have been able to show that human tendon consists of at least eight sub-populations of cells. In addition to endothelial cells, Tc cells, and macrophages, there are five distinct tenocyte populations expressing COL1A genes. These consist of a population of resident cells expressing microfibril associated genes (FBN1, VCAN, DCN, EMILIN1, MFAP5), a group of SCX+ cells co-expressing high levels of pro-inflammatory markers, a population of APOD+ fibro-adipogenic progenitors (FAPs), TPPP3/PRG4+ chondrogenic cells (COMP, CILP, PRG4) and ITGA7+ Smooth Muscle-Mesenchymal Cells, recently described in mouse muscle but not, as yet, in human tendon. Surface proteomic analysis identified markers by which these sub-classes could be isolated and targeted in future.In comparison to healthy tendon, diseased tendon harboured a greater proportion of SCX+ tendon cells and these expressed high levels of proinflammatory markers including CXCL1, CXCL6, CXCL8, PDPN and previously undescribed PTX3. We were also able to show that whereas disease associated genes such as CD248 and PDPN were expressed by COL1+ tenocytes, IL33 was restricted to endothelial cells of chronically diseased tendon.

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“…Recently, there has been increasing evidence documenting the involvement of HMGB1 in musculoskeletal disease 23‐27 . These studies suggest diverse biological functions of HMGB1, including the involvement in both promotion of inflammation and tissue repair 15,23,24,27 . To our knowledge, no reviews have compared the role of HMGB1 in different musculoskeletal diseases.…”

Section: Introductionmentioning

confidence: 99%

The potential roles of high mobility group box 1 (HMGB1) in musculoskeletal disease: A systematic review

et al. 2020

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There is increasing evidence for the involvement of high mobility group box 1 (HMGB1) in inflammation, angiogenesis, and tumorigenesis. However, no studies have reviewed the role of HMGB1 in musculoskeletal disease. This systematic review aimed to evaluate the literature regarding the potential roles of HMGB1 in musculoskeletal disease (joint, tendon, ligament, intervertebral disk, and bone). After searching PubMed, MEDLINE, and EMBASE databases up to 01‐01‐2020, 66 articles that measured HMGB1 expression in musculoskeletal disease were included. Immune and tissue‐resident stromal cells expressed HMGB1, and both diseased human tissues and animal disease models showed increased HMGB1 expression relative to controls. Administration of recombinant HMGB1 to diseased musculoskeletal tissues induced inflammation, whereas blocking HMGB1 ameliorated histopathologic and clinical severity of disease. HMGB1 redox status was investigated in only 3% of the articles: Fully reduced HMGB1 promoted chemotaxis of leukocytes and tissue repair, whereas disulfide HMGB1 acted as a pro‐inflammatory mediator. Our review highlights that while HMGB1 is an important mediator in musculoskeletal disease, its redox status remains understudied. Identification of HMGB1 redox status in musculoskeletal tissues is critical to advance understanding of the diverse biological functions of HMGB1 in musculoskeletal disease. Importantly, this will inform future therapeutic strategies to target HMGB1.

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Differential expression of alarmins—S100A9, IL-33, HMGB1 and HIF-1α in supraspinatus tendinopathy before and after treatment

Cited by 29 publications

References 46 publications

HMGB1 mediates the development of tendinopathy due to mechanical overloading

HMGB1 mediates the development of tendinopathy due to mechanical overloading

Identification of human tendon cell populations in healthy and diseased tissue using combined single cell transcriptomics and proteomics

The potential roles of high mobility group box 1 (HMGB1) in musculoskeletal disease: A systematic review

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