Basic FGF mediates an immediate response of articular cartilage to mechanical injury

Vincent, Tonia L.; Hermansson, Monika; Bolton, Mark; Wait, Robin; Saklatvala, Jeremy

doi:10.1073/pnas.122033199

Cited by 205 publications

(236 citation statements)

References 41 publications

(32 reference statements)

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“…A study applying compressive loading to immature bovine tissue measured increased synthesis and activity of MMP-2 and MMP-9 after 1-16 hours of loading, while no change was measured in TIMP-1 or TIMP-2 synthesis (34). Porcine cartilage disks from 3-6-month-old animals subjected to a cutting injury showed an increase in synthesis of MMP-1, MMP-3, and TIMP-1, while collagen synthesis remained unchanged (35). Interestingly, our study revealed changes in the expression of MMPs and TIMPs, but no change in type II collagen expression.…”

Section: Discussioncontrasting

confidence: 42%

Mechanical injury of cartilage explants causes specific time‐dependent changes in chondrocyte gene expression

Lee

Fitzgerald

DiMicco

et al. 2005

Arthritis & Rheumatism

198

172

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Objective. Joint injury in young adults leads to an increased risk of developing osteoarthritis (OA) later in life. This study was undertaken to determine if injurious mechanical compression of cartilage explants results in changes at the level of gene transcription that may lead to subsequent degradation of the cartilage.Methods. Cartilage was explanted from the femoropatellar groove of newborn calves. Levels of messenger RNA encoding matrix molecules, proteases, their natural inhibitors, transcription factors, and cytokines were assessed in free swelling control cultures as compared with cartilage cultures at 1, 2, 4, 6, 12, and 24 hours after application of a single injurious compression.Results. Gene-expression levels measured in noninjured, free swelling cartilage varied over 5 orders of magnitude. Matrix molecules were the most highly expressed of the genes tested, while cytokines, matrix metalloproteinases (MMPs), aggrecanases (ADAMTS-5), and transcription factors showed lower expression levels. Matrix molecules showed little change in expression after injurious compression, whereas MMP-3 increased ϳ250-fold, ADAMTS-5 increased ϳ40-fold, and tissue inhibitor of metalloproteinases 1 increased ϳ12-fold above the levels in free swelling cultures. Genes typically used as internal controls, GAPDH and ␤-actin, increased expression levels ϳ4-fold after injury, making them unsuitable for use as normalization genes in this study. The expression levels of tumor necrosis factor ␣ and interleukin-1␤, cytokines known to be involved in the progression of OA, did not change in the chondrocytes after injury. Conclusion.Changes in the level of gene expression after mechanical injury are gene specific and time dependent. The quantity of specific proteins may be altered as a result of these changes in gene expression, which may eventually lead to degradation at the tissue level and cause a compromise in cartilage structure and function.

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Section: Discussioncontrasting

confidence: 42%

Mechanical injury of cartilage explants causes specific time‐dependent changes in chondrocyte gene expression

Lee

Fitzgerald

DiMicco

et al. 2005

Arthritis & Rheumatism

198

172

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“…Our results suggest that other FGFs do not compensate for the loss of FGF-2 in adult cartilage. This may be because of the high relative abundance of FGF-2 in articular cartilage compared with other FGFs, and also because of the mechanical control of its bioavailability, which ensures that FGF-2-mediated signaling occurs during weight bearing as well as following chondral injury (7,8).…”

Section: Discussionmentioning

confidence: 99%

“…Upon loading, FGF-2 is made available to cell surface tyrosine kinase receptors and activates intracellular signaling pathways including ERK, one of the MAPKs (7). FGF-2 is also released from the pericellular pool upon physical injury to the tissue (8).…”

mentioning

confidence: 99%

Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS‐5 and delays cartilage degradation in murine osteoarthritis

Chia¹,

Sawaji²,

Burleigh³

et al. 2009

Arthritis & Rheumatism

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182

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Objective. We have previously identified in articular cartilage an abundant pool of the heparin-binding growth factor, fibroblast growth factor 2 (FGF-2), which is bound to the pericellular matrix heparan sulfate proteoglycan, perlecan. This pool of FGF-2 activates chondrocytes upon tissue loading and is released following mechanical injury. In vitro, FGF-2 suppresses interleukin-1-driven aggrecanase activity in human cartilage explants, suggesting a chondroprotective role in vivo. We undertook this study to investigate the in vivo role of FGF-2 in murine cartilage.Methods. Basal characteristics of the articular cartilage of Fgf2 -/-and Fgf2 ؉/؉ mice were determined by histomorphometry, nanoindentation, and quantitative reverse transcriptase-polymerase chain reaction. The articular cartilage was graded histologically in aged mice as well as in mice in which osteoarthritis (OA) had been induced by surgical destabilization of the medial meniscus. RNA was extracted from the joints of Fgf2 -/-and Fgf2 ؉/؉ mice following surgery and quantitatively assessed for key regulatory molecules. The effect of subcutaneous administration of recombinant FGF-2 on OA progression was assessed in Fgf2 -/-mice.Results. Fgf2 -/-mice were morphologically indistinguishable from wild-type (WT) animals up to age 12 weeks; the cartilage thickness and proteoglycan staining were equivalent, as was the mechanical integrity of the matrix. However, Fgf2 -/-mice exhibited accelerated spontaneous and surgically induced OA. Surgically induced OA in Fgf2 -/-mice was suppressed to levels in WT mice by subcutaneous administration of recombinant FGF-2. Increased disease in Fgf2 -/-mice was associated with increased expression of messenger RNA of Adamts5, the key murine aggrecanase. Conclusion. These data identify FGF-2 as a novel endogenous chondroprotective agent in articular cartilage.The structural integrity of articular cartilage is determined principally by homeostasis of the 2 major macromolecules of the extracellular matrix, type II collagen and the chondroitin sulfate-rich proteoglycan aggrecan. In healthy tissue, there is a balance between anabolic (synthetic) and catabolic (degradative) processes that allows matrix turnover. Excessive catabolic activity results in matrix breakdown, a hallmark of osteoarthritis (OA). One key early event in matrix breakdown is loss of aggrecan, which is caused by aggrecanase enzymes, members of the ADAMTS family. In humans, ADAMTS-4 and ADAMTS-5 are thought to be the major aggrecanases in cartilage (1,2). In the mouse, deletion of ADAMTS-5, but not ADAMTS-4, was shown to protect against the development of OA and inflammatory arthritis, suggesting that ADAMTS-5 is the main murine aggrecanase (3,4).We have identified fibroblast growth factor 2 (FGF-2) as a potential regulatory molecule in articular cartilage. It is bound to the heparan sulfate chains of the proteoglycan perlecan in the pericellular matrix of hu-

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“…In cartilage, bFGF is produced by chondrocytes, stored in the ECM, and immediately released from the ECM upon cartilage injury (Vincent et al, 2002;Vincent et al, 2004). Several studies have shown a potent mitogenic impact of bFGF in growth plate cartilage (Rosselot et al, 1994) and adult articular cartilage (Osborn et al, 1989;Stewart et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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

Ellman

Muddasani

et al. 2008

Gene

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131

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Basic FGF mediates an immediate response of articular cartilage to mechanical injury

Cited by 205 publications

References 41 publications

Mechanical injury of cartilage explants causes specific time‐dependent changes in chondrocyte gene expression

Mechanical injury of cartilage explants causes specific time‐dependent changes in chondrocyte gene expression

Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS‐5 and delays cartilage degradation in murine osteoarthritis

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

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