Background

Recently, a larger number of elderly individuals with osteoporosis has undergone total knee arthroplasty (TKA). Intuitively, such vulnerable bone condition should deteriorate post-TKA functional recovery compared to a non-osteoporotic condition, but this hypothesis has not been directly examined.

Background

Acromegaly, which stems from high level of serum growth hormone secreted by a benign tumour in the anterior pituitary gland, is likely to cause severe peripheral joint pains due to hypertrophic changes in such joints. Recently, the life expectancy of such patients has been improved and more patients with acromegaly have undergone joint surgeries to mitigate joint pain and malfunctions. However, little is known about to what extent surgical procedures can improve the joint functions of acromegalic patients compared to non-acromegalic cases.

The term developmental dysplasia of the hip (DDH) describes a spectrum of disorders that results in abnormal development of the hip joint. If not treated successfully in childhood, these patients may go on to develop hip symptoms and/or secondary osteoarthritis in adulthood. In this review we describe the altered anatomy encountered in adults with DDH along with the management options, and the challenges associated with hip arthroscopy, osteotomies and arthroplasty for the treatment of DDH in young adults.

Cite this article: Bone Joint J 2013;95-B:732–7.

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.

Osteoarthritis (OA) is characterized by progressive erosion of articular cartilage due to degradation of the cartilage matrix. The major enzymes involved are the matrix metalloproteases and aggrecanases, which are either derived from the synovium or synthesized by chondrocytes as OA progresses. This abnormal enzyme synthesis is part of a phenotypic change from normal to ‘degradative’ chondrocytes. If this change could be prevented, then disease progression might be slowed.

In early OA, degradative chondrocytes are only present in the superficial zone, but with increasing severity of OA, more chondrocytes become degradative cells so that, in high-grade OA, these cells are also located in the deep zone. We hypothesized the existence of a ‘factor X’, which diffuses from the superficial to the deep zone and induces cells to change phenotype and express the pro-teases. We further hypothesize that this factor is released by degradative chondrocytes. To test the hypothesis, we co-cultured explants of human superficial-zone OA cartilage (which contains degradative cells and thus factor X) with explants of deep-zone cartilage from fracture neck of femur patients (#NOF), which contains mostly normal chondrocytes that do not express the proteases. We investigated MMP expression by real time RT-PCR and protein synthesis by immunohistochemistry.

Before culture, MMP-2, -3, -9, or -13 were expressed in the superficial-zone OA cartilage, but not in deep-zone #NOF cartilage, as expected. After 4 weeks with separate culture of superficial zones and deep zones, no MMPs was expressed in deep zone chondrocytes, suggesting that culture per se did not induce expression of these enzymes. Neither did culture abolish expression in the superficial zone, as confirmed by RT-PCR and immunohistochemistry. However, when superficial-zone cartilage was co-cultured with deep-zone cartilage, MMP-3 expression were induced in deep- zone chon-drocytes, suggesting that a diffusible factor X, derived from degradative chondrocytes, had induced normal articular chondrocytes to express MMP-3. These experiments provide evidence for the existence of a factor that, when diffusing through the cartilage matrix, has the potential to induce normal non-enzyme expressing cells to become degradative chondrocytes.

In the pubertal growth plate, sex hormones play important roles for the regulation of the proliferation, differentiation, maturation and programmed death of chondrocytes. Many studies have been reported on the regulation of oestrogen in long bone growth, however, some of the mechanisms have remained unclarified to date including its role for cell kinetics in the growth plate chondrocytes. The aim of this study was to clarify the effect of the deficiency of oestrogen on growth plate chondrocytes.

We obtained the growth plates of femoral head from the normal and ovariectomized Japanese white rabbits at 10, 15, 20 and 25 weeks. Ovariectomy was performed at 8 weeks. The cell kinetics of chondrocytes as defined by the numbers of proliferating and programmed dying cells was investigated using immunohistological methods.

The lengths of the femur were almost same both in the ovariectomised and normal rabbits. The height of the growth plate was larger in the former. The total number of chondrocytes in the ovariectomised rabbits was less than that of normal rabbits of the same age. Immunostaining of proliferating cell nucleous antigen (PCNA) showed a decrease number of proliferating chondrocytes and that of caspase-3 indicated a little increased number of apoptotic chondrocytes.

Oestrogen regulates endochondral bone formation through several pathways. It directly binds oestrogen receptor alpha and beta, and the former accelerates longitudinal bone growth whereas the latter represses it. Another pathway is through the GH-IGF-I axis: it closely interacts with GH and IGF-I for the control of longitudinal bone growth. In addition, there might be other mediators including transforming growth factor-beta, other IGFs and still unknown paracrine or auto-crine factors as IHH PTHrP. Our study suggests that in the rabbit growth plate during puberty, oestrogen mainly acts through the GH-IGF-I axis since its defi-ciency declined the proliferating ability of chondrocytes, which led the decrease of the number of chondrocytes.

Idiopathic osteoarthritis (OA) is a complex, late-onset disease whose causes are still unknown. In spite of tremendous efforts, the search for the genes pre-disposing towards osteoarthritis has so far met with little success. We hypothesize that epigenetic changes play a major role in the pathology of OA. Epigenetics refers to stable, heritable, but potentially reversible modifications of gene expression that do not involve mutations in the DNA sequence, for example DNA methylation or histone modification. Epigenetic changes are gene and cell-type specific, may arise sporadically with increasing age or be provoked by environmental factors. To investigate whether epigenetic changes are significant factors in OA, we examined the DNA methylation status of the promoter regions of three genes that are expressed by OA, but not by normal, articular chondrocytes, namely MMP-3 (stromelysin-1), MMP-9 (gelatinase B) and MMP-13 (collagenase3). We hypothesized that these genes are silenced in normal chondrocytes by methylation of the cytosines of CpG dinucleotides in the respective promoter regions, but that abnormal expression is associated with a de-methylation, leading to eunsilencing f of gene expression. Cartilage was obtained from the femoral heads of 16 OA and 10 femoral neck fracture (#NOF) patients, which served as controls due to the inverse relationship between osteoporosis and OA. The cartilage was milled in a freezer mill with liquid nitrogen, DNA was extracted with a Qiagen kit, digested with methylation sensitive restriction enzymes, followed by PCR amplification. These enzymes will cut at their specific cleavage sites only if the CpGs is not methylated and thus allow us to determine methylation status of specific CpG sites.

Results. Less than 5% of the chondrocytes in superficial layer from #NOF cartilage expressed degradative enzymes, whereas all cloned chondrocytes from advanced-stage OA cartilage were immunopositive. The overall % of CpG demethylation in the promoters of control patients (whose chondrocytes did not express the enzymes) was 20.1%, whereas 48.6% of CpG sites were demethylated in degradative chondrocytes of OA patients (p< 0.001). For MMP-13, the increase in demethylation between control and OA was from 4 ^..20%; for MMP-9 from 47 ^..81% and for MMP-3 from 30 ^..57%. However, not all available CpG sites were equally demethylated. Some sites were uniformly methylated in both OA and controls, others were demethylated even in controls. However, there was at least one crucial site for each degradative enzyme, where the differences in the degree of methylation were greatest and statistically different. These sites were at −110 for MMP-13; −36 for MMP-9; −635 for MMP-3. There was no relation between the % demethylation and the patient fs age and no apparent difference between males and females.

Conclusions: We have demonstrated an association between abnormal gene expression of MMP-3, MMP-9 and MMP-13 and promoter DNA demethylation. This epigenetic dysregulation of genes appeared to be clonally inherited by daughter cells and may be typical for osteoarthritis and other complex, late-onset diseases.

In osteoarthritis (OA) there is a loss of matrix components, especially aggrecan, which is a major structural component important for the integrity and function of articular cartilage. The breakdown of aggrecan is mediated by enzymes from the ADAM-TS (a disintegrin and metalloproteinase with thrombospondin motifs) family and recent studies have suggested that, in humans, ADAM-TS4 (aggrecanase-1) plays a major role. Articular chondrocytes do not express ADAM-TS4 in contrast to clonal OA chondrocytes. Since in any somatic cell non-expressed genes are thought to be silenced by DNA methylation in the promoter region, the aims of the project were twofold:

to localize enzyme expression for ADAM-TS4 by immunocytochemistry and

Using immunocytochemistry, we confirmed that there is an increased expression of ADAM-TS4 in OA chondrocytes, which initially occurs in chondrocytes of the superficial zone. As the Mankin score increases, ADAM-TS4 positive chondrocytes were found in duplets, then quadruplets until, at Mankin score > 10, all the cells in a typical OA clone were immunopositive for ADAM-TS4, suggesting that abnormal enzyme expression was inherited by daughter cells. DNA was extracted from femoral head cartilage of 24 patients, who had undergone hip replacement surgery for either symptomatic OA or following a fracture of neck of femur (#NOF). The latter was used as control due to the inverse relationship between OA and osteoporosis. For OA samples, it was important to sample only those regions for which immunocytochemistry had shown the presence of ADAM-TS4 synthesizing cells, i.e. the superficial zones near the weight-bearing region. DNA methylation only occurs at cytosines of the sequence 5′...CG...3′, the so-called CpG sites. To determine methylation status of specific CpG sites, methylation sensitive restriction enzymes were used, which will only cut DNA in the absence of methylation. By designing PCR primers that bracketed these sites, presence or absence of PCR bands could distinguish between methylated and non-methylated CpGs respectively. The ADAM-TS4 promoter contains a total of 13 CpG sites. Using restriction enzyme/primers combinations, it was possible to analyze 7 of these sites for methylation status. In the control group, all 7 CpG sites were methylated, while there was an overall 49% decrease of methylation in the OA group (p=< 0.0001). Some of the CpG sites were more consistently demethylated then others, one site at −753bp upstream from the transcription start site, showed a 86% decrease in methylation in OA compared to the control group (p=0.0005), while at other sites the decrease in methylation ranged from 36–50%. Conclusions. This study confirmed by immunocytochemistry that ADAM-TS4 is produced by OA chondrocytes, contributing to the degradation of their matrix. This abnormal enzyme expression is associated with DNA methylation. If a causal relationship could be proven in the future, then DNA de-methylation might play an important role in the pathogenesis of osteoarthritis and future therapies might be directed at influencing the methylation status.

The efficacy of traction before an attempted closed reduction for patients with developmental dislocation of the hip remains controversial. We treated 55 children (62 dislocations of the hip) by preliminary, prolonged traction for a mean of eight weeks. All were followed up for at least two years in order to observe the development of any avascular changes within the femoral head. Of the 55 children, 27 (31 dislocations) were followed up until they were over six years of age. Fifty-seven of the 62 hips (92%) showed a successful closed reduction. Only one had radiological evidence of avascular necrosis of the femoral head. Of the 31 hips which were followed up to over six years of age, 15 (48%) showed residual subluxation. Our method of prolonged preliminary traction leads to a high rate of successful closed reduction, a low incidence of avascular necrosis and a reduced need for secondary operations.

We reviewed 26 patients with 34 shoulders treated by the inferior capsular shift operation for inferior and multidirectional instability. The mean follow-up was 8.3 years. In total, 12 shoulders showed voluntary subluxation. Eight operations used an anterior and posterior approach, 11 were by the posterior route, and 15 shoulders had an anterior approach. In 30 shoulders (85%) the outcome was satisfactory and 20 (59%) scored good or excellent results on the Rowe system. Instability had recurred in nine shoulders (26%) from three months to three years after the operation. Six of the 12 shoulders with voluntary subluxation (50%) had recurrence, as against three of the other 22 (14%), a statistically significant difference. The operation is therefore not indicated for voluntary subluxation.

The 19 shoulders which had been assessed in 1987 at a mean of 3.5 years after surgery, were also reviewed in 1995 and found to have no significant changes in instability or Rowe score. This shows that the capsular shift appeared to have maintained its tension over an eight-year period. After the use of a posterior approach, 64% of the shoulders showed a posterolateral defect on radiographs of the humerus.