Structure/function studies of doxycycline effects on matrix metalloproteinase activity and cartilage degeneration

Abstract

The observation that doxycycline and other tetracyclines reduced the level of matrix metalloproteinase (MMP) activity in periodontal disease, even in germ-free rats [1 2] prompted the testing of these compounds for treatment of osteoarthritis (OA) [3 4], rheumatoid arthritis (for extensive review of this topic see [5-9]) and other diseases in which MMP-mediated destruction of connective tissues is prominent, such as abdominal aortic aneurysms [10] and wound healing in diabetes [11]. Doxycycline and chemically modified tetracyclines have been tested in animal models of OA, a disease in which the degradation of joint connective tissues is thought to depend, at least partially, on MMP activity. In our laboratory, we have employed doxycycline to treat canine experimental OA. We have examined the effect of treatment with oral doxycycline on the MMP of tissues from patients with rheumatoid arthritis, see [5-9], and patients with OA at the time of joint replacement surgery [3]. Similar studies have been performed using minocycline for treatment of adjuvant arthritis in rats [12], and for chemically modified tetracycline-7 (cmt-7) in a spontaneous model of OA in Taft-Hartley guinea pigs [13]. The guinea pig model resembles human disease in that the development of OA is weight-and age-dependent. Treatment with doxycycline slowed disease progression in the animal models, while MMP activity was reduced in both animal and human tissues.