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

Abstract

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-

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

“…The joints in mice deficient of FGF-2 are indistinguishable from wild-type littermates until 12 9 months of ages or with surgical induction of OA, at which point cartilage degradation and increased expression of Adamts5 take place 43 . FGF is normally bound to the heparan sulfate chains of the proteoglycan perlecan in the pericellular matrix, where it acts as a mechanotransducer by activating intracellular others pathways including ERK, one of the MAPKs.…”

“…In articular cartilage, FGF-2 is thought to serve as a chondroprotective agent 43 by suppressing IL-1-or TNF-alpha-stimulated aggrecanase activity. The joints in mice deficient of FGF-2 are indistinguishable from wild-type littermates until 12 9 months of ages or with surgical induction of OA, at which point cartilage degradation and increased expression of Adamts5 take place 43 .…”

Correlation between plasma and synovial fluid basic fibroblast growth factor with radiographic severity in primary knee osteoarthritis

“…The 18-kD human bFGF sequence shares 97% and 99% amino acid identity with mouse/rat and bovine/ovine bFGF, respectively [1,16]. It plays a substantial role in tissue repair and angiogenesis [7] and has been implicated in several experimental models of degenerative joint diseases [6,13,17]. It can promote wound healing and modulate many cellular functions, including proliferation, differentiation and neovascularisation [5].…”

Fibroblast growth factor 2: A new key player in osteoarthritis

“…Thus, ADAMTS-5 appears to be present and poised to act should cartilage become damaged. In the study by Chia et al (1), Fgf2 deletion further enhanced aggrecanase activity. TIMP-3 is the major endogenous inhibitor of aggrecanases known to date (for review, see ref.…”

“…This approach has now paid off in a major way with the discovery that fibroblast growth factor 2 (FGF-2) is a key chondroprotective factor in an OA model, as reported by Chia et al (1) in this issue of Arthritis & Rheumatism.…”