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• W3154334257 abstract "Purpose: Osteoarthritis (OA) is a chronic, debilitating, synovial joint disease that progressively degrades hyaline cartilage. Biochemical, mechanical, metabolic, and genetic factors have been etiologically related to OA. Classically, mechanical injury incites an inflammatory response mediated by a cascade of cytokines produced by a variety of cells including chondrocytes, which activate release of catabolic enzymes from macrophages, neutrophils, lymphocytes and synovial lining cells that degrade the constituents of cartilage responsible for the tissue’s mechanical performance. Most well-characterized models for OA focus on inducing post-traumatic arthritis by creating internal derangement/joint instability or discrete chondral contusions. However, these models require an arthrotomy; surgically violating the joint produces hemarthrosis, which incites synovitis, independent of the biomechanics of the imposed injury. While these models instigate rapid onset of cartilage degradation, they may not replicate the multifaceted clinical nature of OA pathogenesis and treatment. To overcome these shortcomings, we report an animal model for the conditional induction of OA predicated on a common etiology of human gonarthritis, malalignment of the knee mechanical axis which incites OA by applying excessive compression to the cartilage comprising the medial or lateral femoral-tibial compartment. Re-aligning the knee mechanical axis to unload the affected femoral-tibial compartment and decrease the compressive stress has been used clinically for decades, stimulating partial reconstitution of the injured cartilage. Therefore, to incite early OA, without surgically violating the joint integrity, we produced valgus malalignment in the ovine stifle joint using a hinged external fixator (Fig 1A). After 6 weeks, the malalignment was released, simulating surgical correction. Synovial fluid (SF) was analyzed serially for pro-inflammatory cytokines at two-week time intervals for 10 weeks, and contrast-enhanced CT (CECT) imaging using a cationic, iodinated contrast probe, CA4+, to detect tissue glycosaminoglycan (GAG) content was performed at 6 and 28 weeks, thereby enabling quantification of inflammatory and morphological changes induced by altered joint mechanics. Methods: All procedures were approved by the institutional IACUC. After inducing general anesthesia, a hinged external fixator (DePuy Synthes) was mounted laterally across the left femorotibial joint of a skeletally mature female sheep using standard surgical technique. The fixator hinge was aligned co-axial to the isocentric center of rotation of the knee joint, determined dynamically under fluoroscopic guidance. Following drilling of pilot holes into the meta-diaphysis of the distal femur and proximal tibia, four 5mm diameter, self-tapping, hydroxyapatite-coated Schanz screws (SELFDRILL, DePuy Synthes) were inserted to anchor the carbon fiber rods comprising the articulating fixator along the longitudinal axis of the femur and tibia. Genu valgus (12°) was generated by asymmetrically mounting the tibial carbon fiber rod relative to the femur. Local and systemic antibiotics were administered to prevent/treat pin track infection. The knee joint was imaged radiographically at 1, 2 and 4 weeks after surgery to monitor joint malalignment and compression of the lateral femorotibial compartment. At six weeks, the external fixator frame was removed. SF was aspirated from the left stifle joint immediately after placement of the ex-fix apparatus and then every other week for 10 weeks, and from the right stifle joint (contra-lateral control) at 6 and 10 weeks. A pro-inflammatory cytokine immunoassay was performed on all SF samples (MILLIPLEX® Ovine Cytokine/Chemokine Magnetic Bead Panel). Baseline CT imaging (CereTom, Samsung Neurologica) was performed on both knees, followed by intra-articular injection of CA4+ (12 mg I/mL) and repeat CT imaging after 24 hours to reach equilibration (AnalyzeDirect). A two-tailed unpaired t-test (p < .0001) was used for analysis of the CT data (GraphPad Prism). Results: Narrowing of the lateral femorotibial joint space was observed radiographically in response to the applied genu valgum (Fig 1A&B). The malalignment provoked a substantial increase in both plasmatic and synovial fluid levels of proinflammatory cytokines (IL-1α, IL-1β, TNFα, IFNγ, VEGF-A, MIP-1α) over the 6 weeks that the external fixator was in-situ (Fig 1D). The SF concentration of IL-6 increased rapidly over the first four weeks post-op, indicating a strong local inflammatory response to the placement of the fixator. Clinically there was a knee effusion, and the sheep was lame, with only partial weight bearing on the left leg. After fixator removal and release of the applied malalignment, the lameness improved, and the joint effusion resolved. Proinflammatory cytokines in both the plasma and SF returned to normal by week 10, except for IL-4, which remained elevated in the synovium. By 7 months post-surgery, plasmatic levels of IL-10, MIP-1α, and IL-1α increased relative to week 10. CA4+ CECT portrayed a decrease in the GAG content of both the medial and lateral femorotibial compartment cartilage post-surgery (Fig 1C), which continued to decline through the end of the study. At necropsy, there was no synovitis, and the joint cartilage was scored as Outerbridge 0-1 throughout all compartments of both knees. Conclusions: We present a new pre-clinical animal model that induces clinical gonarthritis by producing malalignment of the knee mechanical axis similar to that observed in humans. While reversal of the valgus malalignment Results in return to a normal gait pattern, relief of the knee effusion, and mitigation of proinflammatory cytokines in the synovial fluid linked to OA pathogenesis, the decrease in these markers alone is insufficient to arrest progression of GAG depletion, an early hallmark of OA. The persistence of increased pro-inflammatory biomarker (IL-1α, TNFα, MIP-1α) in plasma is consistent with bone marrow lesions associated with cartilage loss and the GAG depletion observed with CA4+ CECT. On the other end, the persistent increase in cytokines with an anti-inflammatory function, both in plasma (IL-10) and synovial fluid (IL-4), is consistent with the attempt to balance cartilage catabolism and increase chondrocytes’ anabolic activity to restore homeostasis. In conclusion, the results of this pilot study indicate that the correction of pathoanatomy alone may be inadequate to abrogate the deleterious biological effects of the injury on chondrocyte metabolism and anabolic function. The continued loss of GAG even after reversal of the inciting mechanical etiology demonstrates the inability of hyaline cartilage to self-repair. This model enables parametric analysis of the relative effectiveness of: 1) correcting the inciting mechanical etiology; 2) neutralizing catabolic enzymes by arthroscopic joint lavage; 3) abrogating the inflammatory cascade (intra-articular steroids); and 4) reconstituting injured hyaline cartilage by tissue engineering and regenerative medicine interventions." @default.
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• W3154334257 date "2021-04-01" @default.
• W3154334257 modified "2023-09-27" @default.
• W3154334257 title "Valgus malalignment induces osteoarthritis in the ovine stifle joint" @default.
• W3154334257 doi "https://doi.org/10.1016/j.joca.2021.02.237" @default.
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