Fibroblast Growth Factor 23 drives MMP13 expression in human osteoarthritic chondrocytes in a Klotho-independent manner

Bianchi, Arnaud; Guibert, Mathilde; Cailotto, F.; Gasser, Adeline; Presle, Nathalie; Mainard, Didier; Netter, Patrick; Kempf, Hervé; Jouzeau, Jean‐Yves; Reboul, Pascal

doi:10.1016/j.joca.2016.06.003

Cited by 32 publications

(31 citation statements)

References 48 publications

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“…Similarly, it is currently investigated, whether FGF23 can directly affect bone cells in a paracrine manner, and if so, whether this effect requires klotho or not. Interestingly, it has been shown that FGF23 can directly target chondrocytes which lack klotho, and thereby suppress proliferation and induce hypertrophy and differentiation ( 159 , 277 , 278 ). As briefly mentioned before, also macrophages and monocytes ( 215 , 216 , 244 , 245 ) as well as cells in the spleen ( 221 ) can respond to FGF23.…”

Section: Indications That Fgf23 Might Affect a Variety Of Other Tissumentioning

confidence: 99%

FGF23 Actions on Target Tissues—With and Without Klotho

2018

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Fibroblast growth factor (FGF) 23 is a phosphaturic hormone whose physiologic actions on target tissues are mediated by FGF receptors (FGFR) and klotho, which functions as a co-receptor that increases the binding affinity of FGF23 for FGFRs. By stimulating FGFR/klotho complexes in the kidney and parathyroid gland, FGF23 reduces renal phosphate uptake and secretion of parathyroid hormone, respectively, thereby acting as a key regulator of phosphate metabolism. Recently, it has been shown that FGF23 can also target cell types that lack klotho. This unconventional signaling event occurs in an FGFR-dependent manner, but involves other downstream signaling pathways than in “classic” klotho-expressing target organs. It appears that klotho-independent signaling mechanisms are only activated in the presence of high FGF23 concentrations and result in pathologic cellular changes. Therefore, it has been postulated that massive elevations in circulating levels of FGF23, as found in patients with chronic kidney disease, contribute to associated pathologies by targeting cells and tissues that lack klotho. This includes the induction of cardiac hypertrophy and fibrosis, the elevation of inflammatory cytokine expression in the liver, and the inhibition of neutrophil recruitment. Here, we describe the signaling and cellular events that are caused by FGF23 in tissues lacking klotho, and we discuss FGF23’s potential role as a hormone with widespread pathologic actions. Since the soluble form of klotho can function as a circulating co-receptor for FGF23, we also discuss the potential inhibitory effects of soluble klotho on FGF23-mediated signaling which might—at least partially—underlie the pleiotropic tissue-protective functions of klotho.

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Section: Indications That Fgf23 Might Affect a Variety Of Other Tissumentioning

confidence: 99%

FGF23 Actions on Target Tissues—With and Without Klotho

2018

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“…Inhibition of pERK in cultures was able to reduce the hypertrophic induction of articular chondrocytes, in contrast to inhibition of p38 that resulted in hypertrophic induction (Prasadam et al, 2010 ). Furthermore, confirming a role for pERK in hypertrophic processes in OA chondrocytes, ERK1/2 inhibition abolished FGF23-induced MMP13 expression (Bianchi et al, 2016 ).…”

Section: Resultsmentioning

confidence: 73%

“…It has been demonstrated that the expression of FGFR1, FGF23, and its co-receptor KLOTHO is higher in OA chondrocytes compared to non-OA chondrocytes. Expression of these factors was also increased in cartilage samples with more severe macroscopic OA compared to less severe macroscopic OA within the same patient (Bianchi et al, 2016 ). Exogenous addition of FGF23 to human OA primary chondrocytes resulted in hypertrophic changes, as evidenced by COL10A1 and VEGFA induction via FGFR1 (Bianchi et al, 2016 ).…”

Section: Hypoxic and Angiogenic Factorsmentioning

confidence: 99%

“…Expression of these factors was also increased in cartilage samples with more severe macroscopic OA compared to less severe macroscopic OA within the same patient (Bianchi et al, 2016 ). Exogenous addition of FGF23 to human OA primary chondrocytes resulted in hypertrophic changes, as evidenced by COL10A1 and VEGFA induction via FGFR1 (Bianchi et al, 2016 ). Another study confirmed the increase in FGF23 expression levels in OA compared to non-OA chondrocytes (Orfanidou et al, 2009 ).…”

Section: Hypoxic and Angiogenic Factorsmentioning

confidence: 99%

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Recent Insights into the Contribution of the Changing Hypertrophic Chondrocyte Phenotype in the Development and Progression of Osteoarthritis

Ripmeester

Timur

Caron

et al. 2018

Front. Bioeng. Biotechnol.

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Osteoarthritis (OA) is an extremely prevalent age-related condition. The economic and societal burden due to the cost of symptomatic treatment, inability to work, joint replacement, and rehabilitation is huge and increasing. Currently, there are no effective medical therapies that delay or reverse the pathological manifestations of OA. Current treatment options are, without exception, focused on slowing down progression of the disease to postpone total joint replacement surgery for as long as possible and keeping the associated pain and joint immobility manageable. Alterations in the articular cartilage chondrocyte phenotype might be fundamental in the pathological mechanisms of OA development. In many ways, the changing chondrocyte phenotype in osteoarthritic cartilage resembles the process of endochondral ossification as seen, for instance, in developing growth plates. However, the relative contribution of endochondral ossification to the changing chondrocyte phenotype in the development and progression of OA remains poorly described. In this review, we will discuss the current knowledge regarding the cartilage endochondral phenotypic changes occurring during OA development and progression, as well as the molecular and environmental effectors driving these changes. Understanding how these molecular mechanisms determine the chondrocyte cell fate in OA will be essential in enabling cartilage regenerative approaches in future treatments of OA.

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“…After proliferation, chondrocytes present hypertrophic morphology and secrete metal matrix proteinase to facilitate angiopoiesis and the formation of bone collar ( 3 ). However, the pathogenesis of osteoarthritis (OA) is that hyaline cartilages situated in the surface of osteoarticular manifest unbalanced homeostasis and chondrocytes differentiate into hypertrophy ( 4 , 5 ). Additionally, utilizing tissue engineering to repair cartilage defects, the regenerated cartilages are fibrocartilages and the chondrocytes from MSCs express hypertrophic marker protein ( 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

Hypertrophic differentiation of mesenchymal stem cells is suppressed by xanthotoxin via the p38-MAPK/HDAC4 pathway

Cao

Bai

Liu

et al. 2017

Molecular Medicine Reports

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Chondrocyte hypertrophy is a physiological process in endochondral ossification. However, the hypertrophic-like alterations of chondrocytes at the articular surface may result in osteoarthritis (OA). In addition, the generation of fibrocartilage with a decreased biological function in tissue engineered cartilage, has been attributed to chondrocyte hypertrophy. Therefore, suppressing chondrocyte hypertrophy in OA and the associated regeneration of non-active cartilage is of primary concern. The present study examined the effects of xanthotoxin (XAT), which is classified as a furanocoumarin, on chondrocyte hypertrophic differentiation of mesenchymal stem cells. Following XAT treatment, the expression levels of genes associated with chondrocyte hypertrophy were detected via immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction. The results revealed that XAT inhibited the expression of various chondrocyte hypertrophic markers, including runt related transcription factor 2 (Runx2), matrix metalloproteinase 13 and collagen type X α1 chain. Further exploration indicated that XAT reduced the activation of p38-mitogen activated protein kinase and then increased the expression of histone deacetylase 4 to suppress Runx2. The findings indicated that XAT maintained the chondrocyte phenotype in regenerated cartilage and therefore may exhibit promise as a potential drug for the treatment of OA in the future.

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Fibroblast Growth Factor 23 drives MMP13 expression in human osteoarthritic chondrocytes in a Klotho-independent manner

Abstract: These results demonstrate that FGF23 sustains differentiation of OA chondrocytes in a Klotho-independent manner.

Cited by 32 publications

References 48 publications

FGF23 Actions on Target Tissues—With and Without Klotho

FGF23 Actions on Target Tissues—With and Without Klotho

Recent Insights into the Contribution of the Changing Hypertrophic Chondrocyte Phenotype in the Development and Progression of Osteoarthritis

Hypertrophic differentiation of mesenchymal stem cells is suppressed by xanthotoxin via the p38-MAPK/HDAC4 pathway

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