CELLULAR AND EPIGENETIC FEATURES OF OSTEOARTHROSIS IN A 23-YEAR OLD WITH FAILED EARLY SURGICAL TREATMENT OF DEVELOPMENTAL DYSPLASIA OF THE HIP

Abstract

Osteoarthrosis (OA) is often considered to be due to “wear and tear”, aggravated by obesity. However, if developmental dysplasia of the hip (DDH) is treated incorrectly, osteoarthrosis can also occur at a very young age. We obtained cartilage from the femoral head a 23 year-old female after arthroplasty for DDH; from a 14 year-old male, resected for paralytic dislocation, and from OA and control patients. This provided a unique opportunity to compare the cellular and epigenetic features of OA in older patients with those in a young control as well as a DDH patient. We have recently defined the cellular and epigenetic features of idiopathic OA, in particular the association between induction of proteases and loss of DNA methylation in the respective promoter regions (Arthritis Rheum2005; 52: 3110–3124). We had shown that these proteases were silenced in normal articular chondrocytes, but “unsilenced” in OA chondrocytes. The present study determined whether the phenotypic changes of idiopathic OA also take place in juvenile OA and whether loss of DNA demethylation is also associated with the abnormal expression of proteases in juvenile OA. Paraffin sections were immunostained with antibodies to MMP-3, -9, and ADAMTS-4. DNA was extracted from freezer milled cartilage. The methylation status of specific CpG sites (at which methylation occurs) was established using methylation-sensitive restriction enzymes followed by PCR. From the 23 year old female, we only obtained a 1cm thick transverse slice of femur, taken near the femoral neck. However, this contained sufficient reasonably thick cartilage in the perimeter for histology and DNA extraction.

The cartilage of the 14-year old showed high cellularity and absence of immunostaining for all proteases investigated. Apart from the higher cellularity, this was similar to the ‘control’ cartilage obtained from patients with a fracture of the femoral neck. We had previously shown that, as OA progresses, more chondrocytes become immunopositive for the degradative enzymes and these cells divide so that in the typical clones of OA all cells synthesize the proteases. The cartilage from the 23-year old DDH patient showed extensive loss of proteoglycans from the superficial zone and fibrous repair tissue covered some areas. Nearly all chondrocytes produced the proteases and clones had formed, as in idiopathic OA. Since these sample were from the base of the femoral neck, where in idiopathic OA good cartilage often remains even in severe OA, the disease process must have reached an early end-stage in this young patient. The findings indicate that severe OA, as defined by the presence of clones that produce degradative enzymes, can develop very quickly. Interestingly, the expression and synthesis of degradative enzymes by OA chondrocytes was the same in juvenile and old-age OA. and their abnormal expression was associated with “unsilencing” via DNA demethylation in both juvenile and old-age OA. The results thus suggest that age per se is not a major determinant of OA progression.