Emerging therapeutic agents in osteoarthritis

Alcaraz, Marı́a José; Guillén, Marı́a Isabel; Ferrándiz, Marı́a Luisa

doi:10.1016/j.bcp.2019.02.034

Cited by 42 publications

(34 citation statements)

References 126 publications

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“…Osteoarthritis (OA) is the most common chronic joint disease, where the symptoms include pain and loss of mobility of the affected joint, resulting in a significantly reduced quality of life [1]. OA is characterized by the degradation of articular cartilage, which is mediated by an elevated catabolism and an inappropriate repair response of the chondrocytes.…”

Section: Introductionmentioning

confidence: 99%

Increasing the Medium Osmolarity Reduces the Inflammatory Status of Human OA Chondrocytes and Increases Their Responsiveness to GDF-5

Mang

Lindemann

Gigout

2020

IJMS

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The environment surrounding chondrocytes changes drastically in osteoarthritis (OA). For instance, the osmolarity in cartilage (ranging from 350 to 460 mOsm in healthy tissue) decreases during the progression of OA, reaching 270 mOsm. The objective of this study was to evaluate how osmolarity influences human OA chondrocytes. For this purpose, the osmolarity of the culture medium (340 mOsm) was increased to 380, 420 or 460 mOsm and its effect on the phenotype, matrix production, protease expression, cytokine release and growth and differentiation factor-5 (GDF-5) receptor expression in human OA chondrocytes was evaluated in a monolayer. Afterwards, the same parameters, as well as the responsiveness to GDF-5, were evaluated in 3D culture at 340 and 380 mOsm. Our results revealed that increasing the medium osmolarity increased matrix production but also reduced cytokine release, type I collagen and protease expression. It was also demonstrated that at 380 mOsm, the response to GDF-5 in 3D culture was more robust than at 340 mOsm. For the first time, it was established that a decreased osmolarity plays a role in sustaining inflammation and catabolic activities in OA chondrocytes and decreases their responsiveness to GDF-5. This indicates that osmolarity is a critical aspect of OA pathobiology.

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Section: Introductionmentioning

confidence: 99%

Increasing the Medium Osmolarity Reduces the Inflammatory Status of Human OA Chondrocytes and Increases Their Responsiveness to GDF-5

Mang

Lindemann

Gigout

2020

IJMS

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“…Interestingly, both FGF18 and FGF19 genes, encoding for chondrogenic growth factors, were underexpressed, perhaps as the result of BMP2 overexpression. FGF18 is an anabolic chondrogenic and osteogenic growth factor acting through FGFR3 [37,38]. We hypothesize that the underexpression of FGF18 and FGF19 may contribute to further underexpression of genes encoding for core proteins of many proteoglycans, especially those negatively regulated by BMP2 as well (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous, unpublished data found no changes in aggrecan staining in DSLD tendons. By the way, the degradation of articular cartilage in osteoarthritis is thought to be the results of ADAMTS5 and likely also of ADAM TS4 activity [38], two enzymes thought to be involved in degradation of certain SLRPs, e.g., of fibromodulin as well [40]. Though our previous work has demonstrated the presence of modified decorin in tendons with DSLD, it was clear from immunohistochemistry that the majority of the proteoglycan in these tissues was neither decorin nor aggrecan [1,4].…”

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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“…Interestingly, both FGF18 and FGF19 genes, encoding for chondrogenic growth factors, were underexpressed, perhaps as the result of BMP2 overexpression. FGF18 is an anabolic chondrogenic and osteogenic growth factor acting through FGFR3 (31,32). We hypothesize that the underexpression of FGF18 and FGF19 may contribute to further underexpression of genes encoding for core proteins of many proteoglycans, especially those negatively regulated by BMP2 as well (Fig.…”

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 lameness and pain. It is largely unknown what drives the overproduction of proteoglycans, but our previous data 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 (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 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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Emerging therapeutic agents in osteoarthritis

Cited by 42 publications

References 126 publications

Increasing the Medium Osmolarity Reduces the Inflammatory Status of Human OA Chondrocytes and Increases Their Responsiveness to GDF-5

Increasing the Medium Osmolarity Reduces the Inflammatory Status of Human OA Chondrocytes and Increases Their Responsiveness to GDF-5

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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