Objective. To investigate whether the abnormal expression of matrix metalloproteinases (MMPs) 3, 9, and 13 and ADAMTS-4 by human osteoarthritic (OA) chondrocytes is associated with epigenetic "unsilencing."Methods. Cartilage was obtained from the femoral heads of 16 patients with OA and 10 control patients with femoral neck fracture. Chondrocytes with abnormal enzyme expression were immunolocalized. DNA was extracted, and the methylation status of the promoter regions of MMPs 3, 9, and 13 and ADAMTS-4 was analyzed with methylation-sensitive restriction enzymes, followed by polymerase chain reaction amplification.Results. Very few chondrocytes from control cartilage expressed the degrading enzymes, whereas all clonal chondrocytes from late-stage OA cartilage were immunopositive. The overall percentage of nonmethylated sites was increased in OA patients (48.6%) compared with controls (20.1%): 20% versus 4% for MMP-13, 81% versus 47% for MMP-9, 57% versus 30% for MMP-3, and 48% versus 0% for ADAMTS-4. Not all CpG sites were equally susceptible to loss of methylation. Some sites were uniformly methylated, whereas in others, methylation was generally absent. For each enzyme, there was 1 specific CpG site where the demethylation in OA patients was significantly higher than that in controls: at -110 for MMP-13, -36 for MMP-9, -635 for MMP-3, and -753 for ADAMTS-4.Conclusion. This study provides the first evidence that altered synthesis of cartilage-degrading enzymes by late-stage OA chondrocytes may have resulted from epigenetic changes in the methylation status of CpG sites in the promoter regions of these enzymes. These changes, which are clonally transmitted to daughter cells, may contribute to the development of OA.Osteoarthritis (OA) is characterized by the progressive failure of the extracellular cartilage matrix, which leads to the destruction of articular cartilage (1,2). Primary OA is a late-onset complex disease with genetic, mechanical, and environmental components. Concordance of the disease in monozygotic twins is 40-60%, and the overall contribution of genetic factors is estimated to be ϳ50% (3). Given that more than 60% of unrelated adults over the age of 60 years are affected, other factors must also play a role in the development of this disease. Age, obesity, abnormal joint loading, and sports injuries are all risk factors, but OA is more than just the result of "wear and tear" (4,5). Articular chondrocytes are increasingly being suspected of playing major roles in the initiation and progression of the disease (1). This warrants closer examination of the cellular changes that occur in OA.The main extracellular matrix components of articular cartilage are collagens (principally, types II, IX, and XI) and proteoglycans (mainly, aggrecan). The major enzymes that mediate the destructive processes are aggrecanases 1 and 2 (ADAMTS-4 and ADAMTS-5) and matrix metalloproteinases (MMPs) 2 (gelatinase A),

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Metal-on-metal hip bearings are being implanted into younger patients. The consequence of elevated levels of potentially carcinogenic metal ions is therefore a cause for concern. We have determined the levels of cobalt (Co), chromium (Cr), titanium (Ti) and vanadium (Va) in the urine and whole blood of patients who had had metal-on-metal and metal-on-polyethylene articulations in situ for more than 30 years. We compared these with each other and with the levels for a control group of subjects. We found significantly elevated levels of whole blood Ti, Va and urinary Cr in all arthroplasty groups. The whole blood and urine levels of Co were grossly elevated, by a factor of 50 and 300 times respectively in patients with loose metal-on-metal articulations when compared with the control group. Stable metal-on-metal articulations showed much lower levels. Elevated levels of whole blood or urinary Co may be useful in identifying metal-on-metal articulations which are loose.

With the demographics of an aging population the incidence of revision surgery is rapidly increasing. Clinical imperatives to augment skeletal tissue loss have brought mesenchymal stem cells to the fore in combination with the emerging discipline of tissue engineering. Impaction bone grafting for revision hip surgery is a recognized technique to reconstitute bone, the success of which relies on a combination of mechanical and biological factors. The use of morsellized allograft is currently the accepted clinical standard providing a good mechanical scaffold with little osteoinductive biological potential. We propose that applying the principles of a tissue engineering paradigm, the combination of human bone marrow stromal cells (hBMSCs) with allograft to produce a living composite, offers a biological and mechanical advantage over the current gold standard of allograft alone. This study demonstrates that hBMSCs combined with allograft can withstand the forces equivalent to a standard femoral impaction and continue to differentiate and proliferate along the bony lineage. In addition, the living composite provides a biomechanical advantage, with increased interparticulate cohesion and shear strength when compared with allograft alone.

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