Glycan profiling of a defect in decorin glycosylation in equine systemic proteoglycan accumulation, a potential model of progeroid form of Ehlers-Danlos syndrome

Kim, Byoung Jae; Yoon, Jinsu; Zhang, Jian; Mueller, P. O. E.; Halper, Jaroslava

doi:10.1016/j.abb.2010.06.017

Cited by 23 publications

(33 citation statements)

References 52 publications

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“…While research into the molecular pathology of DSLD has focused on structural extracellular matrix components, such as decorin [27] and aggrecan [1, 5], the studies described here indicate that the pathology is accompanied by a more general metabolic disturbance, characterized by an altered expression/activity of TGFβ-signaling target genes in fibroblastic type cells. While precise details of the metabolic disturbance are unknown, the most definitive data linking the DSLD pathology to TGFβ1-signaling is the approximate 4-fold deficiency (fold-difference in DSLD-Paso /NA-Paso about minus 4) in transcript abundance for 19 signaling target genes ( PTK2B , ATF3 , MAPK14 , ME2 , ACVRL1 , NFIB , EPHB2 , HMOX1 , SMAD6 , FOS , GLI2 , STC2 , ID2 , PPARA , ENG , CREBBP , NFKBIA , BRD2 , TGFBR2 ) in adipose-derived stromal fibroblasts (see Table 1).…”

Section: Discussionmentioning

confidence: 95%

“…Such a specific alteration in the TGFβ signaling pathway is entirely in keeping with the pathology of the DSLD-affected ligament, namely extensive scar-like remodeling of the ligament itself (“ S1 Fig”), and altered matrix proteoglycan composition [5, 27]. Indeed the proteoglycan changes observed, including increased total aggrecan [5] and 6-sulfation of N-acetyl galactosamine [27] are established downstream effects of altered TGFβ signaling in connective tissues in general [7, 28–31]. However, the detailed molecular mechanism underlying the altered TGFβ1 responses in the affected horses remain to be established.…”

Section: Discussionmentioning

confidence: 99%

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Degenerative Suspensory Ligament Desmitis (DSLD) in Peruvian Paso Horses Is Characterized by Altered Expression of TGFβ Signaling Components in Adipose-Derived Stromal Fibroblasts

et al. 2016

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Equine degenerative suspensory ligament desmitis (DSLD) in Peruvian Paso horses typically presents at 7–15 years and is characterized by lameness, focal disorganization of collagen fibrils, and chondroid deposition in the body of the ligament. With the aim of developing a test for disease risk (that can be used to screen horses before breeding) we have quantified the expression of 76 TGFβ-signaling target genes in adipose-derived stromal fibroblasts (ADSCs) from six DSLD-affected and five unaffected Paso horses. Remarkably, 35 of the genes showed lower expression (p<0.05) in cells from DSLD-affected animals and this differential was largely eliminated by addition of exogenous TGFβ1. Moreover, TGFβ1-mediated effects on expression were prevented by the TGFβR1/2 inhibitor LY2109761, showing that the signaling was via a TGFβR1/2 complex. The genes affected by the pathology indicate that it is associated with a generalized metabolic disturbance, since some of those most markedly altered in DSLD cells (ATF3, MAPK14, ACVRL1 (ALK1), SMAD6, FOS, CREBBP, NFKBIA, and TGFBR2) represent master-regulators in a wide range of cellular metabolic responses.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Degenerative Suspensory Ligament Desmitis (DSLD) in Peruvian Paso Horses Is Characterized by Altered Expression of TGFβ Signaling Components in Adipose-Derived Stromal Fibroblasts

et al. 2016

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“…DSLD is a debilitating disorder affecting the suspensory ligaments in horses of several breeds, [10][11][12][13] characterized by collagen disruption, accumulation of interfibrillar PGs and chondroid metaplasia. Similar pathologies, including the accumulation of PGs [14][15][16] have been reported in diseased human tendons and ligaments.…”

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confidence: 99%

Biochemical identification and immunolocalizaton of aggrecan, ADAMTS5 and inter‐alpha‐trypsin–inhibitor in equine degenerative suspensory ligament desmitis

Plaas

Sandy

Liu

et al. 2011

Journal Orthopaedic Research

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We describe analysis of suspensory ligaments from horses with advanced degenerative suspensory ligament desmitis (DSLD) to identify the major proteoglycans (PGs), ADAMTS-aggrecanases and inter-alpha-trypsin inhibitor (IaI) components associated with ligament degeneration. Specific anatomical regions of suspensory ligaments from two normal horses and four diagnosed with DSLD were analyzed by Western blot and immunohistochemistry for the following: aggrecan, aggrecan fragments, decorin, ADAMTS4, ADAMTS5, and IaI components. When compared to normal, DSLD ligaments showed about a 15-fold increase (P < 0.0014) in aggrecan levels and markedly enhanced staining with Safranin O. The aggrecan was composed of two distinct high molecular weight core protein species. The largest species was found only in DSLD samples and it co-migrated with aggrecan synthesized by equine mesenchymal stem cells (MSC). Many of the DSLD samples also contained abnormally high concentrations of ADAMTS4, ADAMTS5, and IaI. Notably, the ADAMTS5 in DSLD samples, but not normals, was present largely as a high molecular weight complex. We conclude that ligament degeneration in DSLD is associated with matrix changes characteristic of an inflammatory nonhealing wound, specifically containing chondrogenic progenitor cells. Since aggrecan accumulation is a major feature of incomplete healing in tendon and skin of the ADAMTS5 knockout mouse, we propose that ligament failure in DSLD results from a process involving tissue inflammation and the complexation of ADAMTS5. ß

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“…In recent years, DSLD has been recognised as a systemic disorder characterised by inappropriate proteoglycan presence in organs and structures with high content of connective tissue ( Fig ) and often resulting in progressive lameness, pain and difficulty ambulating (Kim et al . ). In many cases cartilage metaplasia has also been noted; however, calcifications are uncommon and the presence of ossified foci has not been previously reported (Kim et al .…”

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confidence: 97%

Dystrophic mineralisation in degenerative suspensory ligament desmitis

Halper

Mueller

2017

Equine Veterinary Education

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Glycan profiling of a defect in decorin glycosylation in equine systemic proteoglycan accumulation, a potential model of progeroid form of Ehlers-Danlos syndrome

Cited by 23 publications

References 52 publications

Degenerative Suspensory Ligament Desmitis (DSLD) in Peruvian Paso Horses Is Characterized by Altered Expression of TGFβ Signaling Components in Adipose-Derived Stromal Fibroblasts

Degenerative Suspensory Ligament Desmitis (DSLD) in Peruvian Paso Horses Is Characterized by Altered Expression of TGFβ Signaling Components in Adipose-Derived Stromal Fibroblasts

Biochemical identification and immunolocalizaton of aggrecan, ADAMTS5 and inter‐alpha‐trypsin–inhibitor in equine degenerative suspensory ligament desmitis

Dystrophic mineralisation in degenerative suspensory ligament desmitis

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