LEP and obesity due to melanocortin 4 receptor deficiency: Clinically, higher leptin levels in plasma, serum and synovial fluid have been associated with increased pain, radiographic progression, bone formation biomarkers (osteocalcin and PINP), cartilage volume loss and incidence of knee OA [54], detailing this hormone as fundamental to understanding the pathophysiological link between obesity, insulin resistance and OA.