Profibrotic mediators in tendon disease: a systematic review

Morita, Wataru; Snelling, Sarah; Dakin, Stephanie G.; Carr, Andrew

doi:10.1186/s13075-016-1165-0

Cited by 47 publications

(51 citation statements)

References 61 publications

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“…The cytokines of the TGF-β superfamily were excluded as we have reviewed these previously. 12 Studies that compared the expression of the cytokines in diseased human tendon tissues and animal models of tendon injury or exercise with that of healthy control tissue were included. The tendon tissues included in the search criteria were from the mid-substance of tendon or tendon-to-bone enthesis.…”

Section: Methodsmentioning

confidence: 99%

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Cytokines in tendon disease

Morita

Dakin

Snelling

et al. 2017

Bone & Joint Research

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ObjectivesEmerging evidence indicates that tendon disease is an active process with inflammation that is critical to disease onset and progression. However, the key cytokines responsible for driving and sustaining inflammation have not been identified.MethodsWe performed a systematic review of the literature using MEDLINE (U.S. National Library of Medicine, Bethesda, Maryland) in March 2017. Studies reporting the expression of interleukins (ILs), tumour necrosis factor alpha (TNF-α) and interferon gamma in diseased human tendon tissues, and animal models of tendon injury or exercise in comparison with healthy control tissues were included.ResultsIL-1β, IL-6, IL-10, and TNF-α are the cytokines that have been most frequently investigated. In clinical samples of tendinopathy and tendon tears, the expression of TNF-α tended not to change but IL-6 increased in tears. Healthy human tendons showed increased IL-6 expression after exercise; however, IL-10 remained unchanged. Animal tendon injury models showed that IL-1β, IL-6, and TNF-α tend to increase from the early phase of tendon healing. In animal exercise studies, IL-1β expression showed a tendency to increase at the early stage after exercise, but IL-10 expression remained unchanged with exercise.ConclusionsThis review highlights the roles of IL-1β, IL-6, IL-10, and TNF-α in the development of tendon disease, during tendon healing, and in response to exercise. However, there is evidence accumulating that suggests that other cytokines are also contributing to tendon inflammatory processes. Further work with hypothesis-free methods is warranted in order to identify the key cytokines, with subsequent mechanistic and interaction studies to elucidate their roles in tendon disease development.Cite this article: W. Morita, S. G. Dakin, S. J. B. Snelling, A. J. Carr. Cytokines in tendon disease: A Systematic Review. Bone Joint Res 2017;6:656–664. DOI: 10.1302/2046-3758.612.BJR-2017-0112.R1.

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Section: Methodsmentioning

confidence: 99%

“…The quality of study methodology was assessed in all papers by referring to the modified scoring system by Dean et al 8 and Morita et al 12 in order to highlight the studies with a high risk of potential bias. The median score was 8 (interquartile range, 7 to 9) out of 10 (supplementary table iv).…”

Section: Methodsmentioning

confidence: 99%

Cytokines in tendon disease

Morita

Dakin

Snelling

et al. 2017

Bone & Joint Research

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“…Dysregulation of action of TGFβ and related molecules, such as BMPs (BMP2, BMP4, and BMP6) and CTGF (a mediator of BMP activity) in damaged tendons has been well documented in human and animal tendinopathies where the excessive presence of BMPs can lead to increased synthesis and deposition of proteoglycans in the tendon [29,34]. CTGF (encoding for CTGF/ CCN2) is active in chondrocytes and plays important roles in wound healing and fibrotic processes [35].…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression in skin RNA of horses affected with degenerative suspensory ligament desmitis

et al. 2020

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Background Equine degenerative suspensory ligament desmitis (DSLD) is a systemic connective tissue disorder first identified in Peruvian Paso horses but afflicting other horse breeds as well. Inappropriate accumulation of proteoglycans in connective tissues, most prominently in tendons and ligaments, leads to progressive and debilitating lameness and pain. It is largely unknown what drives the overproduction of proteoglycans, but our previous studies suggest involvement of bone morphogenetic protein 2 (BMP2), a member of the transforming growth factor-β (TGFβ) family, impacting synthesis of proteoglycans. To identify potential players in pathogenesis of DSLD a new approach utilizing next generation sequencing was undertaken. Methods Next generation sequencing was performed using RNA extracted from skin biopsies of six control Peruvian Pasos and six horses with DSLD (4 Peruvian Pasos and 2 warmbloods). The CuffDiff result sets were validated with algorithms used to run them. This was based on the determined false discovery rates derived from the P values adjusted for multiple testing for any given result. Results Bioinformatics analysis of transcriptomes revealed differential expression of over 1500 genes, including increased expression of genes for several growth factors (most prominently BMP2, FGF5, CTGF, many members of the EGF family), and mediators of signaling (Fos, Myc, MAPK system), and keratins. Two genes encoding for enzymes involved in synthesis of hyaluronan were also overexpressed. Gene expression was decreased for protein cores of many proteoglycans, several growth factors, most collagens, and many peptides with immune function. Conclusions The overexpression of BMP2 correlates well with our previous data. However, the decrease in expression of numerous proteoglycans was unexpected. A mutation in a gene of a less characterized proteoglycan and/or glycosyltransferase with subsequent increased production of hyaluronan and/or a proteoglycan(s) undetected in our study could account for the systemic proteoglycan deposition. Decreased collagen gene expression indicates abnormal connective tissue metabolism. The increased expression of keratin genes and FGF5 supports reports of skin abnormalities in DSLD. Underexpression of immune function genes corresponds with lack of inflammation in DSLD tissues. Finally, though the proteoglycan and/or glycosaminoglycan abundant in DSLD has not been identified, we validated our previous data, including overexpression of BMP2, and systemic nature of DSLD due to disturbed metabolism of the extracellular matrix.

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“…Dysregulation of action of TGFβ and related molecules, such as BMPs (BMP2, BMP4 and BMP6) and CTGF (a mediator of BMP activity) in damaged tendons has been well documented in human and animal tendinopathies where the excessive presence of BMPs can lead to increased synthesis and deposition of proteoglycans in the tendon (29,34). CTGF (encoding for CTGF/CCN2) is active in chondrocytes, and plays important roles in wound healing and brotic processes (35).…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression in skin RNA of horses affected with degenerative suspensory ligament desmitis

Haythorn¹,

Young²,

Stanton³

et al. 2020

Preprint

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Background Equine Degenerative Suspensory Desmitis (DSLD) is a systemic connective tissue disorder first identified in Peruvian Paso horses, but afflicting other horse breeds as well. Inappropriate accumulation of proteoglycans in connective tissues, most prominently in tendons and ligaments leads to progressive and debilitating lameness and pain. It is largely unknown what drives the overproduction of proteoglycans, but our previous studies suggest involvement of bone morphogenetic protein 2 (BMP2), a member of the transforming growth factor β (TGFβ) family, impacting synthesis of proteoglycans. To identify potential players in pathogenesis of DSLD a new approach utilizing next generation sequencing was undertaken. Methods Next generation sequencing was performed using RNA extracted from skin biopsies of six control Peruvian Pasos and six horses with DSLD (4 Peruvian Pasos and 2 Warmbloods). The CuffDiff result sets were validated with algorithms used to run them. This was based on the determined False Discovery Rates derived from the P-values adjusted for multiple testing for any given result. Results Bioinformatics analysis of transcriptomes revealed differential expression of over 1500 genes, including increased expression of genes for several growth factors (most prominently BMP2, FGF5, CTGF, members of the EGF family), of mediators of signaling (Fos, Myc, MAPK system), and keratins. Two genes encoding for enzymes involved in synthesis of hyaluronan were also overexpressed. Gene expression was decreased for protein cores of many proteoglycans, several growth factors, most collagens and many peptides with immune function. Conclusions The overexpression of BMP2 correlates well with our previous data. However, the decrease in expression of numerous proteoglycans was unexpected. A mutation in a gene of a less characterized proteoglycan and/or glycosyltransferase with subsequent increased production of hyaluronan and/or a proteoglycan(s) undetected in our study could account for the systemic proteoglycan deposition. Decreased collagen gene expression indicates abnormal connective tissue metabolism. The increased expression of keratin genes and FGF5 supports reports of skin abnormalities in DSLD. Underexpression of immune function genes corresponds with lack of inflammation in DSLD tissues. Finally, though the proteoglycan and/or glycosaminoglycan abundant in DSLD has not been identified, we validated our previous data, including overexpression of BMP2 , and systemic nature of DSLD due to disturbed metabolism of the extracellular matrix.

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Profibrotic mediators in tendon disease: a systematic review

Cited by 47 publications

References 61 publications

Cytokines in tendon disease

Cytokines in tendon disease

Differential gene expression in skin RNA of horses affected with degenerative suspensory ligament desmitis

Differential gene expression in skin RNA of horses affected with degenerative suspensory ligament desmitis

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