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.

中文翻译：

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强力霉素对基质金属蛋白酶的抑制作用影响前十字韧带破裂后创伤性骨关节炎的进展：在新型非手术鼠ACL破裂模型中的评估。

背景技术强力霉素作为基质金属蛋白酶（MMP）抑制剂具有广谱活性，因此可以减少前十字韧带（ACL）破裂后创伤后骨关节炎（PTOA）的进展。假设多西环素会在鼠ACL破裂模型中抑制PTOA的进展。研究设计受控的实验室研究。方法在体外研究中，尸体C57BL / 6雄性小鼠膝盖（N = 108）用于建立非手术ACL破裂模型。为了进行体内研究，然后用我们的手动程序对24只C57BL / 6雄性小鼠进行ACL破裂，分为4组：未治疗的对照组；未治疗的对照组；未治疗的对照组。强力霉素，10 mg / kg / d; 强力霉素，50 mg / kg / d; 和强力霉素，100 mg / kg / d。ACL破裂后立即开始在饮用水中施用强力霉素。在第3、7、14和28天评估放射线成像和爪印。分析脚的长度和脚趾的伸展作为功能的量度。在第4周进行组织学和MMP-13免疫组化。结果X线片显示ACL破裂后胫骨前半脱位和半月板挤压，证实膝关节不稳定且无骨折。在完整组和实验组之间，步态在统计学上有显着差异。组织学检查表明，ACL破裂后软骨损伤，半月板撕裂和轻度骨关节炎，与人类患者相似。发现内侧和外侧半月板的后角肥大，并且半月板的后角的泪是常见的。所有强力霉素组的得分均低于未治疗的对照组，表明软骨损伤较少。与3个强力霉素组相比，未治疗组的胫骨后软骨损伤最多，未治疗组和50-mg / kg / d强力霉素组之间存在显着差异，这表明后者剂量可防止蛋白聚糖的丢失和减少。骨关节炎的进展。在所有组中，非强力霉素组的滑膜炎症评分最高，表明强力霉素对滑膜炎具有抑制作用。在强力霉素治疗组的胫骨上MMP-13表达明显降低，强力霉素浓度与MMP-13抑制之间呈正相关。结论强力霉素处理对MMP-13活性的调节可能为减少ACL破裂后PTOA的进展提供了新的生物学途径。临床相关性强力霉素是一种经过批准的，易于获得的药物，很少有光敏性和胃肠道症状的副作用。未来的临床试验可能会评估强力霉素以减少或预防ACL破裂后进行性软骨损伤。