Abstract
ABSTRACTJoint injury is the predominant risk factor for post‐traumatic osteoarthritis development (PTOA). Several non‐invasive mouse models mimicking human PTOA investigate molecular mechanisms of disease development; none have characterized the inflammatory response to this acute traumatic injury. Our aim was to characterize the early inflammatory phase and later degenerative component in our in vivo non‐invasive murine model of PTOA induced by anterior cruciate ligament (ACL) rupture. Right knees of 12‐week‐old C57Bl6 mice were placed in flexion at a 30° offset position and subjected to a single compressive load (12N, 1.4 mm/s) to induce ACL rupture with no obvious damage to surrounding tissues. Tissue was harvested 4 h post‐injury and on days 3, 14, and 21; contralateral left knees served as controls. Histological, immunohistochemical, and gene analyzes were performed to evaluate inflammatory and degenerative changes. Immunohistochemistry revealed time‐dependent expression of mature (F4/80 positive) and inflammatory (CD11b positive) macrophage populations within the sub‐synovial infiltrate, developing osteophytes, and inflammation surrounding the ACL in response to injury. Up‐regulation of genes encoding acute pro‐inflammatory markers, inducible nitric oxide synthase, interleukin‐6 and interleukin‐17, and the matrix degrading enzymes, ADAMTS‐4 and MMP3 was detected in femoral cartilage, concomitant with extensive cartilage damage and bone remodelling over 21‐days post‐injury. Our non‐invasive model describes pathologically distinct phases of the disease, increasing our understanding of inflammatory episodes, the tissues/cells producing inflammatory mediators and the early molecular changes in the joint, thereby defining the early phenotype of PTOA. This knowledge will guide appropriate interventions to delay or arrest disease progression following joint injury. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:2118–2127, 2018.
Highlights
Unlike primary/idiopathic osteoarthritis (OA), the predominant risk factor for development of secondary, often referred to as post-traumatic osteoarthritis (PTOA) is joint injury
CD11b expressing cells were present within the subsynovial cellular infiltrate 3-days after anterior cruciate ligament (ACL) rupture (Fig. 2B), with their abundance in the infiltrate increasing by day-14 (Fig. 2D) when they were detected in the developing osteophyte
We have described a non-invasive model of PTOA whereby a single, 12N load at 1.4 mm/s caused a midsubstance rupture of the ACL, the most commonly reported type of ACL tear.[30]
Summary
Unlike primary/idiopathic osteoarthritis (OA), the predominant risk factor for development of secondary, often referred to as post-traumatic osteoarthritis (PTOA) is joint injury. Type I PTOA models of ACL rupture, typically induced by a single episode of compressive load to the lower limb (12N, 1 mm/s), are characterized by extensive loss of trabecular bone, osteophyte formation and loss of articular cartilage proteoglycans, concomitant with fissuring and chondrocyte apoptosis in the superficial zone over an 8-week period post-induction of injury.[9] Increasing the loading rate from 1 mm/s in this model, which induces an avulsion fracture,[9] to 500 mm/s which results in a mid-substance tear, leads to substantial joint degeneration and an OA phenotype.[15] Alternatively, multiple cycles of tibial compressive load have been used to rupture the ACL and damage the articular surface resulting in PTOA with similarities to human disease.[14] Type I PTOA, caused by ACL rupture, generates a significant inflammatory response; it is thought that PTOA progression is correlated with the inflammatory profile as opposed to the sole contribution of one mediator.[16] Following mechanical insult, inflammatory mechanisms are hypothesized to instigate development and progression of joint degeneration including cellular infiltration, production of cytokines and chemokines, release/activation of proteolytic enzymes, chondrocyte apoptosis, subchondral bone remodeling including osteophyte production, synovial fibrosis and activation of other pathways that mediate tissue catabolism.[17,18] Some of these biological effects instigated at the time of trauma, can propagate a sustained response, weeks to months post-injury and are thought to contribute to PTOA development.[19]
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