title: 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.
authors: Department of Orthopedics and Rehabilitation, University of Iowa, 2181 Westlawn Building, Iowa City 52242, Iowa.|Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa.
authors: James A
authors: JA
authors: Martin
authors: Department of Orthopedics and Rehabilitation, University of Iowa, 2181 Westlawn Building, Iowa City 52242, Iowa.|Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa.
authors: Donald D
authors: DD
authors: Anderson
authors: Department of Orthopedics and Rehabilitation, University of Iowa, 2181 Westlawn Building, Iowa City 52242, Iowa.|Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa.
authors: Jessica E
authors: JE
authors: Goetz
authors: Department of Orthopedics and Rehabilitation, University of Iowa, 2181 Westlawn Building, Iowa City 52242, Iowa.
authors: Douglas
authors: D
authors: Fredericks
authors: Department of Orthopedics and Rehabilitation, University of Iowa, 2181 Westlawn Building, Iowa City 52242, Iowa.|Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa.
authors: Douglas R
authors: DR
authors: Pedersen
authors: Department of Orthopedics and Rehabilitation, University of Iowa, 2181 Westlawn Building, Iowa City 52242, Iowa.|Department of Mathematics, University of Iowa, Iowa City, Iowa.
authors: Bruce P
authors: BP
authors: Ayati
authors: Department of Orthopedics and Rehabilitation, University of Iowa, 2181 Westlawn Building, Iowa City 52242, Iowa.
authors: J Lawrence
authors: JL
authors: Marsh
authors: Department of Orthopedics and Rehabilitation, University of Iowa, 2181 Westlawn Building, Iowa City 52242, Iowa.|Iowa City Veterans Administration Medical Center, Iowa City, Iowa.
authors: Joseph A
authors: JA
authors: Buckwalter
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007596:Joints / Q000293:injuries*; D008954:Models, Biological; D010003:Osteoarthritis / Q000209:etiology*; D014947:Wounds and Injuries / Q000150:complications*
keywords: animal models; chondrocytes; computational models; joint trauma; post-traumatic osteoarthritis