Pathobiological analysis of developmental dysplasia of the hip and its progression to osteoarthritis
Authors:   , Wolfe Preston 
Published: February 2023

Developmental dysplasia of the hip (DDH) is recognized as one of the leading causes of early-onset hip osteoarthritis and a primary reason for undergoing total hip arthroplasty prior to 50 years of age. Even with an increase in awareness and focus on infant screening and early diagnosis, approximately 15-25 percent of DDH cases remain undiagnosed into early adulthood when prevention is no longer possible, interventions are more invasive, and joint degeneration has begun. To improve screening and early diagnosis methods for DDH, the pathobiological mechanisms associated with this disorder must be further characterized. Therefore, the programmatic research plan for this dissertation investigated molecular biology, mechanobiology, biomechanics, and cell- and tissue-based disease mechanisms associated with DDH during its development and progression to secondary hip osteoarthritis. The primary objective for this body of work was to comprehensively characterize these stages of DDH in order to elucidate mechanistic biomarkers for diagnosis, staging, and treatment monitoring as well as targets for novel prevention and treatment strategies. The first experiment in the dissertation research focused on clinically relevant biomechanics of the hip in order to characterize the relevant contributions from key soft tissue structures in maintaining hip stability. The data from this experiment indicated that the ligamentum teres of the femoral head and the acetabular labrum each play important and unique roles in hip joint stability. The ligamentum teres primarily supported anterior stability during increased hip flexion while the labrum primarily supported lateral stability during hip flexion and abduction. The second set of experiments focused on the molecular biology of key intra-articular tissues of the hip by analyzing mechanistic metabolic responses in cell and tissue culture. First, metabolic responses related to hip osteoarthritis were characterized and analyzed for trends with histopathology severity scoring. The results indicated that each tissue type has a unique metabolic profile. Interestingly, the acetabular labrum was associated with robust inflammatory, degradative, immune cell recruitment, and anabolic responses during early degeneration followed by a pronounced anti-degradative response in late degeneration. Subsequent experiments used cells from canine DDH tissues to investigate mechanobiology-related responses prior to the onset of hip osteoarthritis. The results indicated that the ligamentum teres is a primary producer of inflammatory and immune cell recruitment proteins with labral cells also producing significant amounts of these proteins in response to supraphysiologic tensile loading. Interestingly, physiologic loading of dysplastic cells normalized their metabolic response profiles to match those of healthy hips, indicating that dysplastic metabolic responses can be reversible in earlier stages of disease. The final set of experiments for the dissertation focused on analysis of serum and urine from age-matched healthy individuals and those with symptomatic DDH prior to degeneration in order to elucidate mechanistic biomarker panels for differentiating hip status prior to the development of osteoarthritis. Patients with DDH prior to degeneration had significantly different serum and urine biomarker profiles compared to healthy-hip controls and patients with hip osteoarthritis. The primary differences involved increases in inflammatory biomarkers and decreases in bone metabolism, degradation, and anabolism biomarkers. When these proteins were combined into panels, there was excellent discriminatory capability for multiple serum and urine protein panels. Taken together, this series of experiments provides novel molecular biology, mechanobiology, biomechanics, and cell- and tissue-based disease mechanisms data for characterizing DDH during its development and progression to secondary hip osteoarthritis. These data suggest that soft tissue structures in the hip, including the ligamentum teres and acetabular labrum, play key biomechanical and biologic roles in maintaining joint homeostasis and responding to the pathomechanisms involved in the development and progression of DDH. The experiments comprising this dissertation provide the foundation for additional translational and clinical studies designed to comprehensively characterize DDH development and progression and elucidate mechanistic biomarkers that can consistently identify individuals with hip dysplasia at its earliest stages such that progression to hip osteoarthritis can be prevented.