Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis

Ellman, Michael B.; An, Howard S.; Muddasani, Prasuna; Im, Hee-Jeong

doi:10.1016/j.gene.2008.04.019

Cited by 152 publications

(142 citation statements)

References 88 publications

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“…Thus, using Baf32 cells specifically expressing FGFR-3IIIc, and variable amounts of FGF-18 and perlecan we previously demonstrated cell signalling and a potent effect on cellular proliferation [15]. Of the FGFR splice variants, we examined FGFR-3IIIc provided optimal results with FGF-18 consistent with published studies on its roles in skeletal development [24,26,27]. Thus, it was logical to further examine the spatiotemporal localisation of these components in the present study.…”

Section: Discussionsupporting

confidence: 71%

Comparative immunolocalisation of perlecan, heparan sulphate, fibroblast growth factor-18, and fibroblast growth factor receptor-3 and their prospective roles in chondrogenic and osteogenic development of the human foetal spine

et al. 2013

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Purpose A comparative immunolocalisation study of perlecan, HS, FGF-18 and FGFR-3 in the 12-20-week gestational age human foetal spine was undertaken to identify spatiotemporal associations between these components to provide insights into prospective roles in spinal development. Methods Comparative immunolocalisations of matrix and cell associated components in Histochoice-fixed paraffinembedded human foetal spinal tissues. Results The 12-14-week-old human foetal spine was a predominantly cartilaginous structure with the discs displaying a relative paucity of proteoglycan compared to the adjacent cartilaginous vertebral rudiments, notochordal remnants were also observed. HS and perlecan had a widespread distribution throughout the spine at 12 weeks, however, FGF-18 was only localised to the outer AF margins and hypertrophic cell condensations in the vertebral bodies. This contrasted with HS distributions at 14-20 weeks, which were prominent in the developing intervertebral disc (IVD). Ossification centres were also evident centrally within the vertebral rudiments surrounded by small columns of hypertrophic chondrocytes which expressed FGFR-3 and FGF-18 and upregulated levels of perlecan. FGF-18 also had a prominent localisation pattern in the developing IVD and the cartilaginous endplate while FGFR-3 was expressed throughout the disc interspace. This suggested roles for perlecan, FGF-18 and FGFR-3 in chondrogenic and osteogenic events which drive discal development and ossification of the vertebral bodies. Conclusions The above data supported a role for FGF-18 in discal development and in the terminal osteogenic differentiation of chondroprogenitor cell populations, which promote vertebral ossification during spinal development.

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Section: Discussionsupporting

confidence: 71%

Comparative immunolocalisation of perlecan, heparan sulphate, fibroblast growth factor-18, and fibroblast growth factor receptor-3 and their prospective roles in chondrogenic and osteogenic development of the human foetal spine

et al. 2013

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“…We therefore performed assays for FGF-2 and PTHrP, both of which are negative regulators of chondrocyte differentiation (32) and MSC chondrogenesis (33). FGF-2 and PTHrP have been shown to severely reduce type X collagen expression, AP activity, and cell enlargement of lower sternal chondrocytes from immature chicken (34,35), and both molecules are soluble factors produced by articular chondrocytes (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Human articular chondrocytes secrete parathyroid hormone–related protein and inhibit hypertrophy of mesenchymal stem cells in coculture during chondrogenesis

Fischer¹,

Dickhut²,

Rickert³

et al. 2010

Arthritis & Rheumatism

231

240

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Objective. The use of bone marrow-derived mesenchymal stem cells (MSCs) has shown promise in cell-based cartilage regeneration. A yet-unsolved problem, however, is the unwanted up-regulation of markers of hypertrophy, such as alkaline phosphatase (AP) and type X collagen, during in vitro chondrogenesis and the formation of unstable calcifying cartilage at heterotopic sites. In contrast, articular chondrocytes produce stable, nonmineralizing cartilage. The aim of this study was to address whether coculture of MSCs with human articular chondrocytes (HACs) can suppress the undesired hypertrophy in differentiating MSCs.Methods. MSCs were differentiated in chondrogenic medium that had or had not been conditioned by parallel culture with HAC pellets, or MSCs were mixed in the same pellet with the HACs (1:1 or 1:2 ratio) and cultured for 6 weeks. Following in vitro differentiation, the pellets were transplanted into SCID mice.Results. The gene expression ratio of COL10A1 to COL2A1 and of Indian hedgehog (IHH) to COL2A1 was significantly reduced by differentiation in HACconditioned medium, and less type X collagen protein was deposited relative to type II collagen. AP activity was significantly lower (P < 0.05) in the cells that had been differentiated in conditioned medium, and transplants showed significantly reduced calcification in vivo. In mixed HAC/MSC pellets, suppression of AP was dose-dependent, and in vivo calcification was fully inhibited. Chondrocytes secreted parathyroid hormonerelated protein (PTHrP) throughout the culture period, whereas PTHrP was down-regulated in favor of IHH up-regulation in control MSCs after 2-3 weeks of chondrogenesis. The main inhibitory effects seen with HACconditioned medium were reproducible by PTHrP supplementation of unconditioned medium.Conclusion. HAC-derived soluble factors and direct coculture are potent means of improving chondrogenesis and suppressing the hypertrophic development of MSCs. PTHrP is an important candidate soluble factor involved in this effect.Due to the limited self-repair capacity of articular cartilage and the lack of efficient pharmacologic treatments for chondral defects, cell-based approaches for articular cartilage regeneration have been developed. One of these approaches, autologous chondrocyte transplantation (ACT), has been used with encouraging clinical results (1-5). For ACT, chondrocytes are harvested by biopsy of a non-weight-bearing region of the damaged joint, expanded ex vivo, and then reinjected into the site of the defect. Among the limitations of ACT are a paucity of the cell source and tissue damage at the donor site, with the risk of emerging osteoarthritis. To overcome these problems, adult mesenchymal stem cells (MSCs) have been proposed as an alternative cell source. MSCs can be easily obtained from different sources, such as bone marrow (6,7) and adipose tissue (8), and possess good proliferation and differentiation potential, including differentiation into a chondrogenic phenotype (8,9).

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“…Indeed, a significant number of previous studies indicate that FGF-2 enhances the proliferation of chondrocytes, whereas extracellular matrix (ECM) degradation is accelerated by this molecule. In contrast, FGF-18 was shown to act as an anabolic factor for chondrocytes, increasing proteoglycan synthesis and type II collagen production (Ellman et al 2008). In addition to these 2 FGF family members, a few other members were shown to play certain roles in cartilaginous tissues (Weksler et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Catabolic effects of FGF-1 on chondrocytes and its possible role in osteoarthritis

El-Seoudi

Kader

Nishida

et al. 2017

J. Cell Commun. Signal.

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Fibroblast growth factor 1 (FGF-1) is a classical member of the FGF family and is produced by chondrocytes cultured from osteoarthritic patients. Also, this growth factor was shown to bind to CCN family protein 2 (CCN2), which regenerates damaged articular cartilage and counteracts osteoarthritis (OA) in an animal model. However, the pathophysiological role of FGF-1 in cartilage has not been well investigated. In this study, we evaluated the effects of FGF-1 in vitro and its production in vivo by use of an OA model. Treatment of human chondrocytic cells with FGF-1 resulted in marked repression of genes for cartilaginous extracellular matrix components, whereas it strongly induced matrix metalloproteinase 13 (MMP-13), representing its catabolic effects on cartilage. Interestingly, expression of the CCN2 gene was dramatically repressed by FGF-1, which repression eventually caused the reduced production of CCN2 protein from the chondrocytic cells. The results of a reporter gene assay revealed that this repression could be ascribed, at least in part, to transcriptional regulation. In contrast, the gene expression of FGF-1 was enhanced by exogenous FGF-1, indicating a positive feedback system in these cells. Of note, induction of FGF-1 was observed in the articular cartilage of a rat OA model. These results collectively indicate a pathological role of FGF-1 in OA development, which includes an insufficient cartilage regeneration response caused by CCN2 down regulation.

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Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis

Cited by 152 publications

References 88 publications

Comparative immunolocalisation of perlecan, heparan sulphate, fibroblast growth factor-18, and fibroblast growth factor receptor-3 and their prospective roles in chondrogenic and osteogenic development of the human foetal spine

Comparative immunolocalisation of perlecan, heparan sulphate, fibroblast growth factor-18, and fibroblast growth factor receptor-3 and their prospective roles in chondrogenic and osteogenic development of the human foetal spine

Human articular chondrocytes secrete parathyroid hormone–related protein and inhibit hypertrophy of mesenchymal stem cells in coculture during chondrogenesis

Catabolic effects of FGF-1 on chondrocytes and its possible role in osteoarthritis

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