Post-Traumatic Osteoarthritis in Mice Following Mechanical Injury to the Synovial Joint

Abstract

We investigated the spectrum of lesions characteristic of post-traumatic osteoarthritis (PTOA) across the knee joint in response to mechanical injury. We hypothesized that alteration in knee joint stability in mice reproduces molecular and structural features of PTOA that would suggest potential therapeutic targets in humans. The right knees of eight-week old male mice from two recombinant inbred lines (LGXSM-6 and LGXSM-33) were subjected to axial tibial compression. Three separate loading magnitudes were applied: 6N, 9N, and 12N. Left knees served as non-loaded controls. Mice were sacrificed at 5, 9, 14, 28, and 56 days post-loading and whole knee joint changes were assessed by histology, immunostaining, micro-CT, and magnetic resonance imaging. We observed that tibial compression disrupted joint stability by rupturing the anterior cruciate ligament (except for 6N) and instigated a cascade of temporal and topographical features of PTOA. These features included cartilage extracellular matrix loss without proteoglycan replacement, chondrocyte apoptosis at day 5, synovitis present at day 14, osteophytes, ectopic calcification, and meniscus pathology. These findings provide a plausible model and a whole-joint approach for how joint injury in humans leads to PTOA. Chondrocyte apoptosis, synovitis, and ectopic calcification appear to be targets for potential therapeutic intervention.

Evidence for Genetic Contribution to Variation in Posttraumatic Osteoarthritis in Mice

“…We have recently shown that mice develop ectopic calcifications (i.e., calcified nodules in and around the synovium) after surgical DMM or mechanical loading . In the present study, we quantified these nodules after joints were scanned by micro‐CT scanner as described previously .…”

Pros and cons of mouse models for studying osteoarthritis

“…One major advantage of this method is that the traumatic load must only be applied a single time to produce the desired results. Rai et al utilized this method to study the pathophysiology of OA in mice and found the progression of the disease to be similar to, albeit faster than, the progression of the disease in humans [52]. Based on the results of their study, they identified chondrocyte apoptosis, synovitis, and ectopic calcification as possible targets for therapeutic interventions [52].…”

“…Naturally occurring X X X X [9][10][11] Genetically modified X X X X [12][13][14][15][16][17][18][19][20][21][22][23][24] Surgically induced (all) X X X X X [25][26][27][28][29][30] Chemically induced (all) X [31][32][33][34][35][36][37][38][39] Non-invasive induction X X X X X [40][41][42][43][44][45][46][47][48][49][50][51][52] [5,8,63,64]…”

Characterization of Post‐Traumatic Osteoarthritis in Rats Following Anterior Cruciate Ligament Rupture by Non‐Invasive Knee Injury (NIKI)

“…In the last 10 years, multiple non‐invasive ACL rupture models have been developed. These models have primarily used mice and rabbits, with a limited number of studies involving rats . Despite being relatively understudied, there are advantages to establishing this injury model in rats, such as their amenability to behavioral tests and their larger size, which can accommodate certain imaging modalities and therapeutic interventions .…”