Doxycycline Promotes Graft Healing and Attenuates Posttraumatic Osteoarthritis After Anterior Cruciate Ligament Reconstruction in a Rat Model
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摘要Background: Doxycycline (Doxy) has been shown to facilitate tendon healing by reducing on-site matrix metalloproteinase (MMP) activity, but its effect on graft healing after anterior cruciate ligament reconstruction (ACLR) has not been investigated, and the therapeutic effect of Doxy in preventing ACLR-induced posttraumatic osteoarthritis (PTOA) is unclear. Hypothesis: Doxy promotes graft healing and alleviates the progression of PTOA after ACLR. Study Design: Controlled laboratory study. Methods: Sprague Dawley rats (n = 74; age, 12-13 weeks; male) that underwent ACLR were divided into untreated control and Doxy treatment (50 mg/kg/d orally until sacrifice) groups. At 2 and 6 weeks after surgery, graft healing was assessed by biomechanical testing, histology, immunohistochemical staining, and micro–computed tomography (μCT). The progression of PTOA was evaluated at 6 weeks by histology, the Mankin score, and immunofluorescence staining of the tibial plateau, and osteophyte formation was evaluated by μCT. Hindlimb weight distribution was evaluated at 6 weeks, and gait patterns were evaluated at 2 and 6 weeks. Intra-articular MMP activity was evaluated at 6 weeks in vivo using an MMP-activatable near-infrared fluorescent probe. Results: Graft healing was enhanced by Doxy treatment, and the ultimate failure load (P =.002) and stiffness of the graft (P =.007) were significantly higher in the Doxy group at week 2. Bone mineral density and bone volume/total volume for both the tibial and the femoral tunnels at week 6 in the Doxy group were significantly higher compared with in the control group (P <.05). The overall graft healing scores were significantly higher in the Doxy group. Doxy treatment enhanced graft integration, intratunnel graft integrity, and collagen birefringence; more collagen types 1 and 10 and less MMP-13 were found at the graft-bone interface. At week 6, the Doxy group had a lower modified Mankin score (P =.033) and showed fewer MMP 13–positive chondrocytes at the articular cartilage surface (P =.002), indicating moderate joint cartilage damage. μCT revealed less osteophyte formation, and gait analysis revealed more symmetric weightbearing and gait patterns, after Doxy treatment at week 6 (P <.05). In vivo imaging with the near-infrared fluorescent probe identified significantly lower intra-articular MMP activity in the Doxy group at week 6 (P =.016). Conclusion: The oral administration of Doxy was able to synchronously promote graft healing and attenuate PTOA in an ACLR rat model. Clinical Relevance: Our results indicated that Doxy, a widely used drug, is potentially beneficial to patients after ACLR.
著者Cao M., Yao S., Zhu X., Ong M.T.Y., Yung P.S.H., Jiang Y.
期刊名稱American Journal of Sports Medicine
出版年份2023
月份2
卷號51
期次2
出版社SAGE Publications Inc.
頁次461 - 475
國際標準期刊號0363-5465
電子國際標準期刊號1552-3365
語言英式英語
關鍵詞ACLR, doxycycline, graft healing, MMP inhibition, osteoarthritis

上次更新時間 2024-09-04 於 00:38