Bone pain in knee osteoarthritis

Abstract

Knee pain is a major source of disability in patients with knee osteo arthritis (OA). Although the mechanism of OA progression has been well documented, pain pathophysiology is largely unknown. Recent accumulating clinical evidence indicates that subchondral bone marrow lesions (BMLs) detected on MRI in knee OA are strongly associated with intense pain. In this review we describes bone pain in knee osteoarthritis clarified by our basic and clinical studies. In basic studies, we clarified nociceptive phenotype alterations of subchondral bone afferents of the distal femur in mono-iodoacetate (MIA)induced OA rats. Two different retrograde tracers were separately injected into the knee joint cavity and the subchondral bone to identify synovium and subchondral bone afferents. OA caused an up-regulation of calcitonin gene-related peptide (CGRP) and tyrosine receptor kinase A (TrkA) in both synovium and subchondral bone afferents. CGRP and TrkA expression in subchondral bone afferents gradually increased over 6 weeks. Furthermore, up-regulation of CGRP and TrkA in subchondral bone afferents displayed a strong correlation with the subchondral bone damage score. Up-regulation of CGRP and TrkA in subchondral bone afferents correlated with subchondral bone damage, suggesting that subchondral bone is a therapeutic target, especially in the case of advanced stage knee OA. In clinical studies, we clarified the association of subchondral BMLs with pain in medial compartment knee osteoarthritis. Total BMLs size were significantly correlated with walking pain (Spearman's r=0.59, p<0.01). As a result of the multi regression analysis, subchondral BMLs became a factor of walking knee pain in the case of advanced stage knee OA (Regression coefficient = 0.75, p<0.01). Subchondral BMLs are potentially therapeutic targets to treat pain associated with subchondral bone in knee osteoarthritis. In conclusion, subchondral bone, in itself, is a therapeutic target, especially in the case of advanced stage knee OA. In particular, BMLs are potentially therapeutic targets to treat joint pain associated with the subchondral bone in OA.