Summary

This study shows a significant reduction in knee adduction moment in patients with medial compartment osteoarthritis, in both the symptomatic and asymptomatic knees. Long-term follow-up studies are required to confirm the effect of treating the asymptomatic side on disease progression.

BACKGROUND

High tibial Osteotomy (HTO) realigns the forces in the knee to slow the progression of osteoarthritis. This study relates the changes in knee joint biomechanics during level gait to glutamate signalling in the subchondral bone of patients pre and post HTO. Glutamate transmits mechanical signals in bone and activates glutamate receptors to influence inflammation, degeneration and nociception in arthritic joints. Thus glutamate signalling is a mechanism whereby mechanical load can directly modulate joint pathology and pain.

Glutamate is a neurotransmitter that transmits mechanical signals in bone (1) and activates glutamate receptors and transporters, in bone, cartilage, meniscus and synovium (2). Glutamate receptor activation influences inflammatory, degenerative and nociceptive pathways in arthritic joints (2). Thus glutamate signalling is a mechanism whereby mechanical load can directly influence joint pathology and pain. We have investigated components of glutamate signalling in the subchondral bone of patients with osteoarthritis to determine which are expressed and whether this varies in anatomical regions subject to different loads. Subchondral bone was sampled from tibial cuts derived from total knee arthroplasty (n=2, TKR, Kellgren Lawrence grade 3) and from tibial drill hole sites from high tibial osteotomy (n=5, HTO, KL grades 2 and 3) for osteoarthritis. RNA was extracted, reverse transcribed and RT-PCR performed for a housekeeping gene GAPDH, a glutamate transporters (EAAT-1, EAAT1ex9skip), glutamate receptors (NR2A and KA1), a bone matrix protein, osteocalcin, and signaling molecules (osteoprotegerin [OPG], RANKL). We found differential mRNA expression in different regions of subchondral bone. In one TKR patient, EAAT-1 expression was significantly reduced in the anterior zone versus the middle or posterior zones of the tibial plateau (ANOVA, p<0.001). HTO bone cores were subdivided medial/lateral and anterior/posterior. Good quality RNA was obtained from bone cores removed from drill holes during HTO surgery, with GAPDH, osteocalcin, EAAT-1, EAAT1ex9skip, NR2A, KA1, OPG and RANKL mRNA expression detected. In one patient, comparison of gene expression in bone cores obtained pre and post HTO revealed that EAAT1ex9skip was rarely detected in post-op bone whereas KA1 was rare in pre-op bone. This differential mRNA expression may be due to the altered loading through the joint caused by the osteotomy, although these on/off differences need to be quantified to confirm this.

We have shown that glutamate transporters and receptors are expressed in human subchondral bone. Activation of these receptors and transporters by the increased synovial fluid concentrations of glutamate released in arthritis will influence pathological changes and nociception. In some patients, glutamate transporter mRNA expression appears to vary with anatomical location in bone, or after HTO surgery, consistent with our original discovery of this transporter as mechanically-regulated in bone (1). If glutamatergic signaling is mechanically regulated in the human knee, this will vary during arthritic disease progression and after joint realignment, providing a direct mechanism linking mechanical loading through the joint to pathology and pain in arthritis.