The purpose of this K08 Mentored Clinical Scientist Research Career Award application is to provide the PI with training in advanced basic science and clinical research techniques. This training will progress him toward his long-term goal of performing independent translational orthopedic rehabilitation research to establish new therapeutic approaches for the treatment of musculoskeletal and joint trauma. The pathophysiological factors that contribute to the initial onset and early progression of post-traumatic osteoarthritis (PTOA) following severe knee trauma, such as anterior cruciate ligament (ACL) rupture, are poorly understood. One factor that may predispose ACL-reconstructed patients to the onset and progression of PTOA is neuromuscular dysfunction of the quadriceps, which develops secondary to the combined catabolic sequelae produced by the index injury, subsequent surgery, and accompanying muscle disuse. Contrasting what is observed with models of uncomplicated disuse, muscular weakness and dysfunctions following ACL-reconstruction are not completely remediated by strength training and orthopedic rehabilitation. This persistent muscle weakness is thought to predispose patients to PTOA by decreasing the ability of the quadriceps to attenuate shock during gait and maintain normal distribution of forces across the tibiofemoral joint. These biomechanical alterations can lead to abnormal contact stresses and loading within the knee, which provoke adaptations in cartilage metabolism that hasten its degradation and the onset and progression of PTOA. Our goal is to address these neuromuscular maladaptations in their infancy through targeting of their root causes with therapeutic interventions. At present, however, the specific cellular and sub-cellular adaptations that occur in muscle to promote strength loss, the associated biomechanical gait alterations, and changes in articular cartilage composition have not been clearly defined. The proposed studies are designed to address this knowledge gap in three specific aims: 1) to determine the effects of acute ACL injury on skeletal muscle function, structure and protein expression at the molecular, cellular, tissue and whole body levels; 2) to define adaptations in gait biomechanics that result from muscle strength loss; and 3) to evaluate the loss of glycosaminoglycan and type-II collagen fibril disruption in the tibiofemoral articular cartilage. T accomplish these goals, we will study 20 ACL-injured subjects with serial assessments of bilateral skeletal muscle strength and function as well as cartilage-specific MRI at pre-surgical baseline and 6-month follow up; and assess 3D gait kinematics at 6 months post-ACL-reconstruction. Results from these studies will advance knowledge by providing novel mechanistic information about the effect of ACL injury and subsequent surgical intervention on skeletal muscle size and function and its relationship to altered gait and cartilage biology in humans. These results have the potential to impact clinical care by informing the development of new interventions to specifically target the cellular and sub-cellular muscle adaptations that contribute to the pathoetiology of PTOA.
A substantial proportion of individuals who rupture their anterior cruciate ligament (ACL) will experience post- traumatic, early onset osteoarthritis. It ha been theorized that the long-term quadriceps strength deficits commonly observed following ACL injury and surgical reconstruction lead to alterations in tibiofemoral articular contact stresses, resulting in the onset and progression of PTOA. The purpose of this study is to investigate the cellular level mechanisms related to strength loss following ACL injury, as well as their association with gait abnormalities and molecular changes within the tibiofemoral articular cartilage with the goal of identifying novel pathoetiological mechanisms and, in turn, therapeutic targets.
