Biomarkers in Osteoarthritis

Osteoarthritis (OA) is a multifactorial disease of the joints, common among older adults, which can lead to pain, impaired function and reduced quality of life. This thesis aims to investigate the associations and predictive value of various hormonal, inflammatory and imaging biomarkers with OA outcomes in population-based studies of people with and without prevalent OA. Two population samples were used in this thesis. The first group was a population-based sample of older adults aged 50-80 years (mean age: 62 years; 51% female). Followup measurements were conducted 2.7 (2.6-3.3) years later and again for questionnaire data 5.0 (5.3-6.8) years later. Magnetic resonance imaging (MRI) on the right knees was undertaken at baseline and first followup: knee cartilage volume, tibial bone area, cartilage defects and bone marrow lesions (BMLs) were measured or scored; cartilage mean T1 signal intensity and thickness were measured by semi-automated software. Baseline knee and hip x-rays were scored for joint space narrowing (JSN) and osteophytes. Serum leptin and cytokine levels were measured by immunoassay at baseline and first followup. Body morphometry was measured at baseline. Fat and lean mass measures were measured at baseline using dual-energy x-ray absorptiometry (DXA). Knee pain was assessed by questionnaires (WOMAC, Western Ontario and McMasters Osteoarthritis Index) at all timepoints. The second group was a population-based sample of younger adults aged 26-51 (mean age 41; 64% female). Anthropometric, x-ray and MRI-derived scores and measures were obtained as in the first group. Urinary C-terminal crosslinking telopeptide of type II collagen (U-CTX-II) was measured by measured by immunoassay. This thesis consists of 6 studies. In the first study, in older adults, circulating levels of both leptin and interleukin-6 (IL-6) were associated with hip JSN in both sexes and females respectively, independently of BMI. Adiposity was associated with hip JSN, but not after adjustment for leptin. In the second study, baseline levels of both IL-6 and tumor necrosis factor alpha (TNF-˜í¬±) were associated with medial tibiofemoral knee JSN. Baseline IL-6, change in IL-6 and change in TNF-˜í¬± were associated with cartilage volume loss. In the third study, in older adults, baseline or change over 2.9 years in circulating levels of high sensitivity C-reactive protein (hs-CRP), IL-6 and TNF-˜í¬± were associated with change over 5 years in sub-scale or total WOMAC knee pain. In the fourth study, higher leptin in older adults was significantly associated with lower femoral, tibial and patellar cartilage thickness. Fat measures were negatively associated with cartilage thickness, largely mediated by leptin. Baseline and change in leptin were associated with medial tibial cartilage thickness loss. In the fifth study, knee cartilage defects in older adults were found to be common, not likely to regress, and to predict cartilage volume loss and risk of knee replacement. In the final study, mean T1 MRI signal intensity of cartilage was negatively associated with BMI and same-region cartilage defects in younger and older adults; with U-CTX-II in younger adults; and with JSN and osteophytes in older adults at various sites. It predicted cartilage thickness loss over 2.7 years in older adults. In conclusion, inflammatory and metabolic factors may play important roles in aetiology of cartilage loss and/or symptoms in OA. Cartilage defects predict cartilage loss and risk of knee replacement, and mean T1 MRI signal intensity of cartilage predicts loss of cartilage thickness. All these are potential biomarkers for OA at risk of development or progression, and thus possible targets for intervention.