Prevention of progressive joint destruction in collagen‐induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR255031

{"type":"entrez-nucleotide","attrs":{"text":"FR255031","term_id":"258061135","term_text":"FR255031"}}FR255031 (2-[(7S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxido-4-(2-pyridinylcarbonyl)hexahydro-1,4-thiazepin-7-yl]-N-hydroxyacetamide) is a novel synthetic matrix metalloproteinase (MMP) inhibitor that inhibits human collagenases (MMP-1, MMP-8 and MMP-13), gelatinases (MMP-2 and MMP-9) and membrane type 1 MMP (MT1-MMP/MMP-14). {"type":"entrez-nucleotide","attrs":{"text":"FR255031","term_id":"258061135","term_text":"FR255031"}}FR255031 also inhibits rat collagenase and gelatinase. We studied the effect of {"type":"entrez-nucleotide","attrs":{"text":"FR255031","term_id":"258061135","term_text":"FR255031"}}FR255031 and Trocade, an inhibitor of collagenase and MMP-14, on a rat collagen-induced arthritis (CIA) model. Rat CIA was induced by intradermal injection of type II collagen (IIC) and oral administration of {"type":"entrez-nucleotide","attrs":{"text":"FR255031","term_id":"258061135","term_text":"FR255031"}}FR255031 or Trocade was performed for 28 days. Body weight loss, hind paw swelling, elevation of serum anti-IIC antibody, and histological and radiographic scores were evaluated. {"type":"entrez-nucleotide","attrs":{"text":"FR255031","term_id":"258061135","term_text":"FR255031"}}FR255031 markedly inhibited cartilage degradation in a dose-dependent manner in the CIA model, but Trocade failed to prevent the degradation. {"type":"entrez-nucleotide","attrs":{"text":"FR255031","term_id":"258061135","term_text":"FR255031"}}FR255031 at a dose of 100 mg kg−1 also had statistically significant effects on bone destruction and pannus formation and on the recovery of body weight loss on day 28. These results indicate that {"type":"entrez-nucleotide","attrs":{"text":"FR255031","term_id":"258061135","term_text":"FR255031"}}FR255031 is effective for rat CIA, especially on joint cartilage destruction. These data suggest that as well as collagenases or MT-MMP, gelatinases are also involved in joint destruction in arthritis. Keywords: Matrix metalloproteinase inhibitor, collagenase, gelatinase, collagen-induced arthritis, pharmacokinetics Introduction Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are involved in connective tissue breakdown both in normal physiological processes, such as development and wound healing (Stamenkovic, 2003), and in several disease states, including atherosclerosis, tumor invasion, ulcerative diseases and arthritic diseases (Fini et al., 1996; Curran & Murray, 1999; Herouy et al., 2000; Mengshol et al., 2002; Jones et al., 2003). Rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic arthritic diseases that result in joint destruction and loss of function. This joint destruction is due, in part, to the degradation of extracellular matrix in articular cartilage, mainly composed of fibrillar type II collagen (IIC) and aggregating proteoglycans (PGs). In the pathogenesis of RA and OA, degradation of cartilage collagen matrix is primarily accomplished by MMPs that include collagenases (MMP-1, MMP-8 and MMP-13), gelatinases (MMP-2 and MMP-9), stromelysins (MMP-3 and MMP-10) and membrane type MMPs (MT-MMPs). Collagenases can cleave the intact triple helix of collagen, at single site three-quarters of the distance from the amino-terminus, under physiological conditions (Brinckerhoff, 1991; Mengshol et al., 2002). Gelatinases are well known for their ability to degrade the basement membrane and partially degraded collagen (gelatin), working in concert with collagenases to digest collagen matrix. Gelatinases are also involved in bone resorption and angiogenesis, which contribute to joint destruction either directly or indirectly (Itoh et al., 1998; Sang, 1998; Koivunen et al., 1999; Delaisse et al., 2000; Jackson et al., 2001). Membrane type 1 MMP (MT1-MMP)/MMP-14 has been identified as an activator of pro-MMP-2 (Strongin et al., 1995). MMP-14 is also called a tethered collagenase since MMP-14 can digest fibrillar collagens like collagenases (Ohuchi et al., 1997; Holmbeck et al., 2004). Clinically, current treatments for RA and OA reduce pain and swelling of the joint but generally do little to block the cartilage degradation underlying these symptoms (Cawston & Rowan, 1998). Although recent anticytokine agents and other biological response modifiers retard the progression of joint damage, the long-term clinical effects of these agents remain to be elucidated. Moreover, these agents are limited due to several problems, such as infectious adverse events, rebound of symptoms, short half-lives or high treatment costs (Bemelmans et al., 1994; Lipsky & Kavanaugh, 1999; Kalden, 2001; Ellerin et al., 2003). Ultimately, this progressive cartilage degradation may leave joint replacement as the only viable therapeutic option. Therefore, there is an urgent need for the development of cartilage protective drugs. Despite the relevance of MMPs to cartilage degradation (Vincenti et al., 1994), few MMP inhibitors have entered clinical trials for RA or OA and none have so far been successful. Trocade is the only MMP inhibitor to have completed clinical trials designed to assess its efficacy, but it did not prevent progression of joint damage in patients with RA (Close, 2001; Jackson et al., 2001). {"type":"entrez-nucleotide","attrs":{"text":"FR255031","term_id":"258061135","term_text":"FR255031"}}FR255031 (2-[(7S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxido-4-(2-pyridinylcarbonyl)hexahydro-1, 4-thiazepin-7-yl]-N-hydroxyacetamide) is a novel synthetic MMP inhibitor, different from Trocade in several characteristics (Figure 1). {"type":"entrez-nucleotide","attrs":{"text":"FR255031","term_id":"258061135","term_text":"FR255031"}}FR255031 inhibits collagenases (MMP-1, MMP-8 and MMP-13), gelatinases (MMP-2 and MMP-9) and MT-MMP (MMP-14) in vitro. In contrast, Trocade is an inhibitor of collagenase and MT-MMP. In the present study, we compared the ability of these two MMP inhibitors to prevent cartilage degradation in rat collagen-induced arthritis (CIA). CIA is an autoimmune arthritis model induced in susceptible strains of mice, rats or monkeys by immunization with IIC (Trentham et al., 1977; Stuart et al., 1979; Courtenay et al., 1980; Trentham, 1982; Hart et al., 1998). This animal model has been widely used to investigate pathogenic mechanisms in RA, such as erosion of bone and articular cartilage, pannus formation and infiltration of inflammatory cells, and also to evaluate potential new therapeutic agents. We demonstrated that {"type":"entrez-nucleotide","attrs":{"text":"FR255031","term_id":"258061135","term_text":"FR255031"}}FR255031 significantly inhibited cartilage degradation in the rat CIA model, although Trocade failed to prevent the degradation. These results suggest that gelatinases, in cooperation with collagenases and MT-MMP, play an important role in cartilage matrix degradation and that inhibition of collagenase, gelatinase and MT-MMP is recommended in the treatment of arthritic joints. Figure 1 Chemical structure of FR255031, a matrix metalloprotease inhibitor. Methods Drugs {"type":"entrez-nucleotide","attrs":{"text":"FR255031","term_id":"258061135","term_text":"FR255031"}}FR255031 and Trocade were prepared at Fujisawa Pharmaceutical Co., Ltd (Ibaraki, Japan).