Osteoarthritis (OA) is a complex disease, now recognized to involve all structural elements of the articulating joint. Different therapies will be required to tackle different aspects of the condition. Cartilage loss associated with OA is a major determinant for joint replacement surgery. Preventing, or even reversing, articular cartilage matrix degradation in OA has long been considered an important therapeutic aim by the research community and the pharmaceutical industry.
There are still a number of hurdles to leap before blocking cartilage matrix breakdown becomes a standard part of OA therapy, but there are good grounds to argue that the cartilage matrix is a relevant, worthwhile target for therapeutics that will improve patient outcomes. Articular cartilage degradation associated with OA is an enzyme-driven process, and is, therefore, an excellent candidate for the development of inhibitory, disease-modifying OA drugs (DMOADs).
Research has concentrated on the two major components of articular cartilage, collagen type II and aggrecan. Collagen II provides cartilage with its tensile strength and aggrecan is responsible for its weight-bearing properties. Together these molecules make up 70–80% of the dry weight of the tissue. The loss of collagen II and aggrecan in OA cartilage is well documented .
Cartilage loss associated with OA is likely to be irreversible due to the poor ability of the tissue to repair the collagen framework. The importance of aggrecan degradation in cartilage erosion was confirmed in a genetically modified mouse strain, in which aggrecan was made resistant to enzymatic degradation; these mice had less aggrecan loss and cartilage erosion in a model of OA .
A wealth of in vitro and in vivo data from both human tissues and animal models have identified specific zinc metalloproteinases as the major mediators of both collagen II and aggrecan loss; matrix metalloproteinase (MMP)-13 is the major collagenase , and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and -5 are the major aggrecanases . The importance of these enzymes is underlined by targeted deletion of either MMP-13  or ADAMTS-5  in mice, which are both resistant to cartilage erosion in a model of OA. One limitation of using ‘knockout’ mice to identify the role of specific proteinases is that enzymatic activity is completely blocked at disease onset, a situation unlikely to be replicated in the treatment of human OA. However, in many patients, the disease remains stable for long periods of time before progressing [7,8], and DMOADs could be used to prevent further cartilage loss. An alternative is to give these drugs prophylactically to patients with acute traumatic joint injury that is likely to lead to OA. Cathepsin K has been implicated in collagen degradation , and calpain  and HtrA1  degrade human aggrecan in vivo, but the significance of these enzymes in OA remains to be determined.
An alternative therapeutic target is tissue inhibitor of metalloproteinase-3, a potent endogenous inhibitor of MMP-13, and ADAMTS-4 and -5 . In the tissue, inhibitor of metalloproteinase-3 knockout mouse, there is significant, spontaneous cartilage degradation, characterized by both collagen and aggrecan loss . A number of small-molecule inhibitors have been developed that target MMP-13 and ADAMTS-4 and -5. The results of previous clinical trials of MMP inhibitors for the treatment of arthritis and cancer were disappointing, as there were side effects, such as muscle soreness and tendonitis, or the drugs showed no benefit .
However, the early MMP inhibitors blocked a number of metalloproteinases, whereas now there are more promising drugs that are more specific for MMP-13 . Cartilage matrix degradation has recently fallen out of favor as a target of OA therapy, even with the development of these potentially useful new DMOADs. A recent review of the Clinical Trials Data Bank revealed only one Phase I clinical trial of an aggrecanase inhibitor (NCT00454298) and no trials involving MMP inhibitors . As of September 2010, this situation had not changed. In the past few years, several OA discovery programs in large pharma have closed down. This is not due to a lack of progress but rather due to difficulties in determining the efficacy of DMOADs on cartilage loss in clinical trials. The major American (US FDA) and European (EMEA) licensing authorities specify joint space narrowing (JSN), caused by cartilage loss, as the primary end point.
However, the rate of JSN is very slow, it can also be caused by meniscal displacement and there are problems with current radiological methods of measuring it , so that improvements can only be determined using very large clinical trials over long time periods that are impractical and prohibitively expensive for the pharmaceutical industry. In response to these issues, the Osteoarthritis Research Society International OMERACT initiative has devised “time to fulfillment of criteria for total joint replacement”  as an alternative end point, specifically for use in clinical trials, as a way of making trials of DMOADs more feasible. “Preventing, or even reversing, articular cartilage matrix degradation in OA has long been considered an important therapeutic aim … There are still a number of hurdles to leap … but there are good grounds to argue that the cartilage matrix is a relevant, worthwhile target for therapeutics that will improve patient outcomes.” Given the difficulties in using imaging techniques to monitor drug efficacy, there is an urgent requirement for biomarkers to chart the progression of articular cartilage damage and the effectiveness of DMOADs; none are currently available. Recently, two new assays [19,20] have been devised that detect aggrecan fragments in serum and urine. Using these assays, increased levels of aggrecan fragments were seen in OA patients [19,20].
It remains to be determined if aggrecan fragments are accurate biomarkers of OA disease progression, but if so, these assays will be valuable not only for clinical trials but for diagnosis and management of the disease. Pain and loss of joint function are the clinical symptoms of most concern to patients. There is conflicting evidence over the relationship between cartilage loss (as measured by JSN) and pain. A recent review of the literature concluded that JSN is an imprecise guide to the presence of pain . However, a subsequent study of two cohorts with a total of over 1000 patients, which minimized confounding factors, showed a strong link between JSN and pain . Recently, intriguing links have been made between matrix degradation and pain in animal models. In the mouse, deletion of ADAMTS-5 activity reduced mechanical allodynia in a model of OA . The mechanism remains unclear but a drug that blocks ADAMTS-5 could improve this major clinical symptom. Similarly, inhibition of cathepsin K in a guinea pig model of spontaneous OA reduced collagen degradation and joint nociception . There is also a suggestion from the trialing of new MMP-13 inhibitors in a rat OA model that pain was reduced . Some tantalizing evidence is therefore emerging that blocking cartilage loss could alleviate pain. Inhibiting MMP-13, and ADAMTS-4 and -5 could have beneficial effects on joint tissues other than articular cartilage.
All three enzymes cleave a number of extracellular matrix and cell surface proteins in vitro [25,26], and all are expressed in bone [27,28] and synovium [29,30], two tissues that are affected in OA and are very likely to be major drivers of the disease [31,32]. In a mouse model of OA, there was less thickening of the subchondral bone plate in ADAMTS-5-deficient mice compared with wild-type mice ; this effect could be due to a lack of ADAMTS-5 activity in the bone. There is evidence that the degradation of cartilage matrix proteins (e.g., collagen II  and fibronectin ) produces bioactive fragments.
For example, fibronectin fragments have biphasic effects on the release from articular cartilage of IL-1 and TNF-a , proinflammatory cytokines that may play important roles in OA [36,37]. Although research in this area has focused on the effects of bioactive matrix protein fragments in cartilage, these fragments readily diffuse from the tissue and are detected in human OA synovial fluid [38,39]. It is interesting to speculate that these fragments might contribute to OA symptoms that could therefore be alleviated by blocking metalloproteinase action. The past decade has seen the interest in cartilage as an OA therapeutic target wane, concomitant with increasing evidence that changes in subchondral bone precede, and might even cause, cartilage erosion . However, the concept that subchondral bone changes drive cartilage loss remains controversial, and both processes could happen independently or influence each other. In the same time period, the research community has made major progress in identifying drug targets and demonstrating in animal models the potential effectiveness of DMOADs directly targeting cartilage breakdown. Hopefully, better, more affordable methodologies and protocols will be developed for clinical trials so that cartilage-preserving DMOADs can become an important part of the arsenal of treatments to manage OA.
- Martel-Pelletier J, Boileau C, Pelletier JP, Roughley PJ: Cartilage in normal and osteoarthritis conditions. Best Pract. Res. Clin. Rheumatol. 22, 351–384 (2008).
- Little CB, Meeker CT, Golub SB et al.: Blocking aggrecanase cleavage in the aggrecan interglobular domain protects against cartilage erosion and promotes cartilage repair. J. Clin. Invest. 117, 1627–1636 (2007).
- Burrage PS, Mix KS, Brinckerhoff CE: Matrix metalloproteinases: role in arthritis. Front. Biosci. 11, 529–543 (2006).
- Fosang AJ, Rogerson FM: Identifying the human aggrecanase. Osteoarthr. Cartil. 18, 1109–1116 (2010).
- Little CB, Barai A, Burkhardt D et al.: Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum. 60, 3723–3733 (2009).
- Glasson SS, Askew R, Sheppard B et al.: Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434, 644–648 (2005).
- Massardo L, Watt I, Cushnaghan J, Dieppe P: Osteoarthritis of the knee joint: an eight year prospective study. Ann. Rheum. Dis. 48, 893–897 (1989).
- Spector TD, Dacre JE, Harris PA, Huskisson EC: Radiological progression of osteoarthritis: an 11 year follow up study of the knee. Ann. Rheum. Dis. 51, 1107–1110 (1992).
- Vinardell T, Dejica V, Poole AR et al.: Evidence to suggest that cathepsin K degrades articular cartilage in naturally occurring equine osteoarthritis. Osteoarthr. Cartil. 17, 375–383 (2009). Editorial Rogerson future science group www.futuremedicine.com 581 Cartilage matrix degradation: an appropriate therapeutic target in osteoarthritis Editorial
- Struglics A, Hansson M: Calpain is involved in C-terminal truncation of human aggrecan. Biochem. J. 430, 531–538 (2010).
- Chamberland A, Wang E, Jones AR et al.: Identification of a novel HtrA1-susceptible cleavage site in human aggrecan: evidence for the involvement of HtrA1 in aggrecan proteolysis in vivo. J. Biol. Chem. 284, 27352–27359 (2009).
- Woessner JF Jr: That impish TIMP: the tissue inhibitor of metalloproteinases-3. J. Clin. Invest. 108, 799–800 (2001).
- Sahebjam S, Khokha R, Mort JS: Increased collagen and aggrecan degradation with age in the joints of Timp3-/- mice. Arthritis Rheum. 56, 905–909 (2007). 14 Overall CM, Kleifeld O: Tumour microenvironment – opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat. Rev. Canc. 6, 227–239 (2006). 15 Baragi VM, Becher G, Bendele AM et al.: A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models. Arthritis Rheum. 60, 2008–2018 (2009).
- Berenbaum F: Targeted therapies in osteoarthritis: a systematic review of the trials on www.clinicaltrials.gov. Best Pract. Res. Clin. Rheumatol. 24, 107–119 (2010).
- Hellio Le Graverand-Gastineau MP: OA clinical trials: current targets and trials for OA. Choosing molecular targets: what have we learned and where are we headed? Osteoarthr. Cartil. 17, 1393–1401 (2009).
- Ornetti P, Brandt K, Hellio Le Graverand-Gastineau MP et al.: OARSI-OMERACT definition of relevant radiological progression in hip/knee osteoarthritis. Osteoarthr. Cartil. 17, 856–863 (2009).
- Swearingen CA, Carpenter JW, Siegel R et al.: Development of a novel clinical biomarker assay to detect and quantify aggrecanasegenerated aggrecan fragments in human synovial fluid, serum and urine. Osteoarthr. Cartil. 18, 1150–1158 (2010).
- Dufield DR, Nemirovskiy OV, Jennings MG et al.: An immunoaffinity liquid chromatography-tandem mass spectrometry assay for detection of endogenous aggrecan fragments in biological fluids: use as a biomarker for aggrecanase activity and cartilage degradation. Anal. Biochem. 406(2), 113–123 (2010).
- Bedson J, Croft PR: The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature. BMC Musculoskelet. Disord. 9, 116 (2008).
- Neogi T, Felson D, Niu J et al.: Association between radiographic features of knee osteoarthritis and pain: results from two cohort studies. BMJ 339, b2844 (2009).
- Malfait AM, Ritchie J, Gil AS et al.: ADAMTS-5 deficient mice do not develop mechanical allodynia associated with osteoarthritis following medical meniscal destabilization. Osteoarthr. Cartil. 18, 572–580 (2010).
- McDougall JJ, Schuelert N, Bowyer J: Cathepsin K inhibition reduces CTXII levels and joint pain in the guinea pig model of spontaneous osteoarthritis. Osteoarthr. Cartil. 18(10), 1355–1357 (2010).
- Folgueras AR, Pendas AM, Sanchez LM, Lopez-Otin C: Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int. J. Dev. Biol. 48, 411–424 (2004).
- Tortorella MD, Malfait F, Barve RA, Shieh HS, Malfait AM: A review of the ADAMTS family, pharmaceutical targets of the future. Curr. Pharm. Des. 15, 2359–2374 (2009).
- Nakamura H, Sato G, Hirata A, Yamamoto T: Immunolocalization of matrix metalloproteinase-13 on bone surface under osteoclasts in rat tibia. Bone 34, 48–56 (2004).
- Nakamura M, Sone S, Takahashi I et al.: Expression of versican and ADAMTS1, 4, and 5 during bone development in the rat mandible and hind limb. J. Histochem. Cytochem. 53, 1553–1562 (2005).
- Vankemmelbeke MN, Holen I, Wilson AG et al.: Expression and activity of ADAMTS-5 in synovium. Eur. J. Biochem. 268, 1259–1268 (2001).
- Fortier LA, Motta T, Greenwald RA, Divers TJ, Mayr KG: Synoviocytes are more sensitive than cartilage to the effects of minocycline and doxycycline on IL-1a and MMP-13-induced catabolic gene responses. J. Orthop. Res. 28, 522–528 (2010).
- Kwan Tat S, Lajeunesse D, Pelletier JP, Martel-Pelletier J: Targeting subchondral bone for treating osteoarthritis: what is the evidence? Best Pract. Res. Clin. Rheumatol. 24, 51–70 (2010).
- Attur M, Samuels J, Krasnokutsky S, Abramson SB: Targeting the synovial tissue for treating osteoarthritis (OA): where is the evidence? Best Pract. Res. Clin. Rheumatol. 24, 71–79 (2010).
- Botter SM, Glasson SS, Hopkins B et al.: ADAMTS5-/- mice have less subchondral bone changes after induction of osteoarthritis through surgical instability: implications for a link between cartilage and subchondral bone changes. Osteoarthr. Cartil. 17(5), 636–645 (2009).
- Jennings L, Wu L, King KB et al.: The effects of collagen fragments on the extracellular matrix metabolism of bovine and human chondrocytes. Connect. Tissue Res. 42, 71–86 (2001).
- Homandberg GA: Potential regulation of cartilage metabolism in osteoarthritis by fibronectin fragments. Front. Biosci. 4, D713–D730 (1999).
- Goldring SR, Goldring MB: The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clin. Orthop. Relat. Res. 427(Suppl.), S27–S36 (2004).
- Bondeson J, Blom AB, Wainwright S et al.: The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive processes in osteoarthritis. Arthritis Rheum. 62, 647–657 (2010).
- Sandy JD, Flannery CR, Neame PJ, Lohmander LS: The structure of aggrecan fragments in human synovial fluid: evidence for the involvement in osteoarthritis of a novel proteinase which cleaves the Glu 373-Ala 374 bond of the interglobular domain. J. Clin. Invest. 89, 1512–1516 (1992).
- Griffiths AM, Herbert KE, Perrett D, Scott DL: Fragmented fibronectin and other synovial fluid proteins in chronic arthritis: their relation to immune complexes. Clin. Chim. Acta 184, 133–146 (1989).