An Explorative Study into the Aetiology of Developmental Dysplasia of the Hip Using Targeted Urine Metabolomics

Abstract

Developmental dysplasia of the hip (DDH) is the most prevalent congenital musculoskeletal disorder, yet its cause remains unknown. Adequate nutrient provision and coordinated electron exchange (redox) processes are critical for foetal growth and tissue development. This novel study sought to explore specific biochemical pathways in skeletal development for potential involvement in the aetiology of DDH. Spot urine samples were collected from infants, aged 13–61 days, with and without DDH. Ion chromatography-mass spectrometry was used to quantify thiosulphate, sulphate, nitrate, and phosphate, whilst nitrite was quantified using high-performance liquid chromato-graphy. Thiobarbituric acid reactive substances (TBARS) were measured as markers of lipid peroxidation. Creatinine and osmolality were determined by a 96-well plate assay and micro-osmometer to potentially normalise values for renal function, lean body mass, and hydration status. Urine samples were analysed from 99 babies: 30 with DDH and 69 age-matched non-DDH controls. Thiosulphate, TBARS, and creatinine concentrations differed between the DDH group and the controls (p = 0.025, 0.015, and 0.004 respectively). Urine osmolality was significantly lower in DDH compared to the controls (p = 0.036), indicative of the production of a more diluted urine in DDH infants. Following adjustment for osmolality, significant differences became apparent in urinary sulphate levels in DDH (p = 0.035) whereas all other parameters were similar between the groups. This is the first study to assess the potential role of these inorganic anions in DDH. The higher levels of sulphate found in infants with DDH suggests either enhanced intake from milk, increased endogenous formation, or impaired renal reabsorption. This investigation demonstrates the power of urine metabolomics and highlights the importance of normalisation for hydration status to disentangle developmental disorders. Our results strongly suggest that DDH is a systemic disease associated with altered uptake, formation, or handling of sulphate. There is potential for new opportunities in the prevention or treatment of DDH via nutritional intervention.

Keywords

• reactive species
• oxidative stress
• hydrogen sulphide
• redox processes
• sulphate
• skeletal development