Complementary models reveal cellular responses to contact stresses that contribute to post-traumatic osteoarthritis

Abstract

Two categories of joint overloading cause post-traumatic osteoarthritis (PTOA): single acute traumatic loads/impactions and repetitive overloading due to incongruity/instability. We developed and refined three classes of complementary models to define relationships between joint overloading and progressive cartilage loss across the spectrum of acute injuries and chronic joint abnormalities: explant and whole joint models that allow probing of cellular responses to mechanical injury and contact stresses, animal models that enable study of PTOA pathways in living joints and pre-clinical testing of treatments, and patient-specific computational models that define the overloading that causes OA in humans. We coordinated methodologies across models so that results from each informed the others, maximizing the benefit of this complementary approach. We are incorporating results from these investigations into biomathematical models to provide predictions of PTOA risk and guide treatment. Each approach has limitations, but each provides opportunities to elucidate PTOA pathogenesis. Taken together, they help define levels of joint overloading that cause cartilage destruction, show that both forms of overloading can act through the same biologic pathways, and create a framework for initiating clinical interventions that decrease PTOA risk. Considered collectively, studies extending from explants to humans show that thresholds of joint overloading that cause cartilage loss can be defined, that to at least some extent both forms of joint overloading act through the same biologic pathways, and interventions that interrupt these pathways prevent cartilage damage. These observations suggest that treatments that decrease the risk of all forms of OA progression can be discovered. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:515-523, 2017.

Keywords: animal models; chondrocytes; computational models; joint trauma; post-traumatic osteoarthritis.

Figure 1. Results of inhibiting mechanical strain-ROS pathway following joint injury: (A) viable chondrocytes/mm³ and (B) chondrocyte ATP (ng/mg) [CTB: cytochlasin B, NOC: nocodazole, AMO: amobarbital]

Figure 2. MRI images of goat knee before and six months after impaction and partial meniscectomy

Figure 3. Intraoperative fluoroscopic images of the creation and surgical repair of an intra-articular fracture of the distal tibia in the Yucatan mini-pig model

Figure 4

The relative proportion of articular surface area experiencing supra-threshold contact stress was perfectly predictive of OA status two years following surgical reduction of displaced intra-articular fractures of the distal tibia.

Figure 5

Plot of changes in visual analog scale (VAS) pain score (post-op – pre-op) vs. change in maximum contact stress. VAS pain scores range from 0 to 10, with higher scores indicating more pain. Lower contact stress values were computed in patients who experienced less pain.