Matrix Metalloproteinase Inhibition With Doxycycline Affects the Progression of Posttraumatic Osteoarthritis After Anterior Cruciate Ligament Rupture: Evaluation in a New Nonsurgical Murine ACL Rupture Model. Issue 1 (January 2020) - Zhang, Xueying
Background: Doxycycline has broad-spectrum activity as a matrix metalloproteinase (MMP) inhibitor and thus could reduce the progression of posttraumatic osteoarthritis (PTOA) after anterior cruciate ligament (ACL) rupture. Hypothesis: Doxycycline would inhibit progression of PTOA in a murine ACL rupture model. Study Design: Controlled laboratory study. Methods: For the in vitro study, cadaveric C57BL/6 male mice knees (N = 108) were used for the development of a nonsurgical ACL rupture model. For the in vivo study, 24 C57BL/6 male mice then underwent ACL rupture with our manual procedure and were divided into 4 groups: untreated control; doxycycline, 10 mg/kg/d; doxycycline, 50 mg/kg/d; and doxycycline, 100 mg/kg/d. Doxycycline was administered in drinking water beginning immediately after ACL rupture. Radiographic imaging and paw prints were evaluated at 3, 7, 14, and 28 days. The foot length and toe spread were analyzed as measures of function. Histology and MMP-13 immunohistochemistry were done at 4 weeks. Results: Radiographs demonstrated anterior tibial subluxation and meniscal extrusion after ACL rupture, confirming knee joint instability without fractures. Statistically significant differences in gait were found between the intact and experimental groups. Histologic examination demonstrated cartilage damage, meniscal tears, and mild osteoarthritis after ACL rupture, similar to what occurs in human patients. Hypertrophy of the posterior horn of the medial and lateral meniscus was found, and tears of the posterior horn of the menisci were common. All doxycycline groups had a lower score than the untreated control group, indicating less cartilage damage. The posterior tibia of the untreated group had the most cartilage damage as compared with the 3 doxycycline groups, with a significant difference between the untreated and 50-mg/kg/d doxycycline groups, suggesting that the latter dose may protect against proteoglycan loss and decrease the progression of osteoarthritis. The nondoxycycline group had the highest synovial inflammation score among all groups, indicating that doxycycline has an inhibitory effect on synovitis. There was significantly lower MMP-13 expression on the tibia in the doxycycline-treated groups, with a positive correlation between doxycycline concentration and MMP-13 inhibition. Conclusion: Modulation of MMP-13 activity by doxycycline treatment may offer a novel biological pathway to decrease the progression of PTOA after ACL rupture. Clinical Relevance: Doxycycline is an approved, readily available drug with infrequent side effects of photosensitivity and gastrointestinal symptoms. Future clinical trials could evaluate doxycycline to reduce or prevent progressive cartilage damage after ACL rupture.