Objectives
While various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/ CCR5 chemokine axes in OA pathogenesis.
Methods
Ccl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains.
Results
Mice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA.
Conclusions
Our findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA.
Sesamoid bones form within tendons in regions that wrap around bony prominences. They are common in humans but variable in number. Sesamoid development is mediated epigenetically by local mechanical forces associated with skeletal geometry, posture, and muscular activity. In this article we review the literature on sesamoids and explore the question of genetic control of sesamoid development. Examination of radiographs of 112 people demonstrated that the relatively infrequent appearances of the fabella (in the lateral gastrocnemius tendon of the knee) and os peroneum (in the peroneus longus tendon of the foot) are related within individuals (P < 0.01). This finding suggests that the tendency to form sesamoids may be linked to intrinsic genetic factors. Evolutionary character analyses suggest that the formation of these sesamoids in humans may be a consequence of phylogeny. These observations indicate that variations of intrinsic factors may interact with extrinsic mechanobiological factors to influence sesamoid development and evolution.
Total knee arthroplasty is a successful procedure to treat pain and functional disability due to osteoarthritis. However, precisely how a total knee arthroplasty changes the kinematics of an osteoarthritic knee is unknown. We used a surgical navigation system to measure normal passive kinematics from 7 embalmed cadaver lower extremities and in vivo intraoperative passive kinematics on 17 patients undergoing primary total knee arthroplasty to address two questions: How do the kinematics of knees with advanced osteoarthritis differ from normal knees?; and, Does posterior substituting total knee arthroplasty restore kinematics towards normal? Osteoarthritic knees displayed a decreased screw-home motion and abnormal varus/valgus rotations between 108 and 908 of knee flexion when compared to normal knees. The anterior-posterior motion of the femur in osteoarthritic knees was not different than in normal knees. Following total knee arthroplasty, we found abnormal varus/valgus rotations in early flexion, a reduced screw-home motion when compared to the osteoarthritic knees, and an abnormal anterior translation of the femur during the first 608 of flexion. Posterior substituting total knee arthroplasty does not appear to restore normal passive varus/valgus rotations or the screw motion and introduces an abnormal anterior translation of the femur during intraoperative evaluation. ß
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