Osteoarthritis is a major source of pain, disability, and socioeconomic cost worldwide. The epidemiology of the disorder is complex and multifactorial, with genetic, biological, and biomechanical components. Aetiological factors are also joint specific. Joint replacement is an effective treatment for symptomatic end-stage disease, although functional outcomes can be poor and the lifespan of prostheses is limited. Consequently, the focus is shifting to disease prevention and the treatment of early osteoarthritis. This task is challenging since conventional imaging techniques can detect only quite advanced disease and the relation between pain and structural degeneration is not close. Nevertheless, advances in both imaging and biochemical markers offer potential for diagnosis and as outcome measures for new treatments. Joint-preserving interventions under development include lifestyle modification and pharmaceutical and surgical modalities. Some show potential, but at present few have proven ability to arrest or delay disease progression.

The extracellularly regulated kinase (ERK), one of the three types of mitogen-activated kinases, was rapidly activated after cutting porcine articular cartilage either when maintained as explants or in situ. Cutting released a soluble ERK-activating factor from the cartilage, which was purified and identified by MS as basic fibroblast growth factor (bFGF). Experiments with neutralizing Abs to bFGF and an FGFR1 tyrosine kinase inhibitor showed that this growth factor was the major ERK-activating factor released after injury. Treating cartilage with the heparin-degrading enzyme heparitinase also caused release of bFGF, suggesting the presence of an extracellular store that is sequestered in the matrix and released upon damage. Basic FGF induced the synthesis of a number of chondrocyte proteins including matrix metalloproteinases 1 and 3, tissue inhibitor of metalloproteinases-1, and glycoprotein 38, which were identified by MS. The strong induction of matrix metalloproteinases and tissue inhibitor of metalloproteinases-1 suggests that bFGF could have a role in remodeling damaged tissue.

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-

Objective. Mechanical joint loading is critical for the development of osteoarthritis (OA). Although once regarded as a disease of cartilage attrition, OA is now known to be controlled by the expression and activity of key proteases, such as ADAMTS-5, that drive matrix degradation. This study was undertaken to investigate the link between protease expression and mechanical joint loading in vivo.Methods. We performed a microarray analysis of genes expressed in the whole joint following surgical induction of murine OA (by cutting the medial meniscotibial ligament). Gene expression changes were validated by reverse transcriptase-polymerase chain reaction in whole joints and microdissected tissues of the joint, including the articular cartilage, meniscus, and epiphysis. Following surgery, mouse joints were immobilized, either by prolonged anesthesia or by sciatic neurectomy.Results. Many genes were regulated in the whole joint within 6 hours of surgical induction of OA in the mouse. These included Arg1, Ccl2, Il6, Tsg6, Mmp3, Il1b, Adamts5, Adamts4, and Adamts1. All of these were significantly regulated in the articular cartilage. When joints were immobilized by prolonged anesthesia, regulation of the vast majority of genes was abrogated. When joints were immobilized by sciatic neurectomy, regulation of selected genes was abrogated, and OA was prevented up to 12 weeks postsurgery.Conclusion. These findings indicate that gene expression in the mouse joint following the induction of OA is rapid and highly mechanosensitive. Regulated genes include the known pathogenic protease ADAMTS-5. Targeting the mechanosensing