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- Title
Doxycycline Promotes Graft Healing and Attenuates Posttraumatic Osteoarthritis After Anterior Cruciate Ligament Reconstruction in a Rat Model.
- Authors
Cao, Mingde; Yao, Shiyi; Zhu, Xiaobo; Ong, Michael T.Y.; Yung, Patrick S.H.; Jiang, Yangzi
- Abstract
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.
- Subjects
WOUND healing; DISEASE progression; STATISTICS; ANIMAL experimentation; IMMUNOHISTOCHEMISTRY; GAIT in humans; DOXYCYCLINE; MANN Whitney U Test; RATS; MATRIX metalloproteinases; T-test (Statistics); OSTEOARTHRITIS; FLUORESCENT antibody technique; DIAGNOSIS; ENZYME-linked immunosorbent assay; DESCRIPTIVE statistics; STATISTICAL hypothesis testing; RESEARCH funding; ANTERIOR cruciate ligament surgery; COMPUTED tomography; BONE density; BIOMECHANICS; DATA analysis software; DATA analysis; TRANSPLANTATION of organs, tissues, etc.
- Publication
American Journal of Sports Medicine, 2023, Vol 51, Issue 2, p461
- ISSN
0363-5465
- Publication type
Article
- DOI
10.1177/03635465221145015