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Osteoarthritis is the most common form of arthritis and a major socioeconomic burden. Our study is the first to explore the association between serum microRNA levels and the development of severe osteoarthritis of the knee and hip joint in the general population. We followed 816 Caucasian individuals from 1995 to 2010 and assessed joint arthroplasty as a definitive outcome of severe osteoarthritis of the knee and hip. After a microarray screen, we validated 12 microRNAs by real-time PCR in the entire cohort at baseline. In Cox regression analysis, three microRNAs were associated with severe knee and hip osteoarthritis. let-7e was a negative predictor for total joint arthroplasty with an adjusted HR of 0.75 (95% CI 0.58 to 0.96; p=0.021) when normalised to U6, and 0.76 (95% CI 0.6 to 0.97; p=0.026) after normalisation to the Ct average. miRNA-454 was inversely correlated with severe knee or hip osteoarthritis with an adjusted HR of 0.77 (95% CI 0.61 to 0.97; p=0.028) when normalised to U6. This correlation was lost when data were normalised to Ct average (p=0.118). Finally, miRNA-885-5p showed a trend towards a positive relationship with arthroplasty when normalised to U6 (HR 1.24; 95% CI 0.95 to 1.62; p=0.107) or to Ct average (HR 1.30; 95% CI 0.99 to 1.70; p=0.056). Our study is the first to identify differentially expressed circulating microRNAs in osteoarthritis patients necessitating arthroplasty in a large, population-based cohort. Among these microRNAs, let-7e emerged as potential predictor for severe knee or hip osteoarthritis.

Although osteoarthritis is characterized by a progressive loss of the extracellular cartilage matrix, very little is known about the fate of articular chondrocytes during the progression of the disease. In this study we examined the expression of syndecan-3, a marker of early chondrocyte differentiation, and annexin VI, a marker of late chondrocyte differentiation, in mammalian embryonic growth plate cartilage and normal and osteoarthritic human articular cartilage. Whereas syndecan-3 was expressed in the proliferative and hypertrophic zones of growth platecartilage, immunostaining for annexin VI waspredominately found in the hypertrophic and mineralizing zones of fetal bovine growth plate cartilage. Approximately 20% of chondrocytes were immunopositive for syndecan-3 in normal human articular cartilage, the number of syndecan-3-expressing chondrocytes significantly increased during the progression of osteoarthritis with more than 80% syndecan-3-positive cells in the upper zone of severely affected osteoarthritic cartilage. Similarly, the number of annexin VI-expressing cells significantly increased in the upper cartilage zones during the progression of osteoarthritis. Furthermore, immunostaining for proliferating cell nuclear antigen, a marker for cell proliferation, was detected in chondrocytes in the upper zone of osteoarthritic cartilage. Double-labeling experiments with antibodies against syndecan-3 and annexin VI revealed chondrocytes that expressed only syndecan-3, and cells that expressed both syndecan-3 and annexin VI. These results suggest that the expression of early (proliferating cell nuclear antigen, syndecan-3) and late differentiation markers (annexin VI, alkaline phosphatase) is activated in chondrocytes of osteoarthritic cartilage.

This study investigated the effect of thrombospondin-1 (TSP-1) on the formation of cartilage repair tissue in combination with stimulation by osteogenic protein-1 (OP-1). In miniature pigs, articular cartilage lesions in the femoral trochlea were treated by the microfracture technique and either received no further treatment (MFX), or were treated by additional application of recombinant osteogenic protein-1 (MFX+OP-1), recombinant TSP-1 (MFX+TSP-1), or a combination of both proteins (MFX+TSP-1+OP-1). Six and 26 weeks after surgery, the repair tissue and the degree of endochondral ossification were assessed by histochemical and immunohistochemical methods detecting collagen types I, II, X, TSP-1, and CD31. Microfracture treatment merely induced the formation of inferior fibrocartilaginous repair tissue. OP-1 stimulated chondrogenesis, but also induced chondrocyte hypertrophy, characterized by synthesis of collagen type X, and excessive bone formation. Application of TSP-1 inhibited inadvertant endochondral ossification, but failed to induce chondrogenesis. In contrast, the simultaneous application of both TSP-1 and OP-1 induced and maintained a permanent, nonhypertrophic chondrocyte-like phenotype within cartilage repair tissue. The data of this study demonstrate that OP-1 and TSP-1 complement each other in a functional manner. While OP-1 induces chondrogenesis of the ingrowing cells, TSP-1 prevents their further hypertrophic differentiation and prevents excessive endochondral ossification within the lesions.

Background: Total knee arthroplasty (TKA) has been established as a successful surgical treatment in the late stages of rheumatoid joint destruction. The purpose of this study was to review the clinical outcome and survivorship in rheumatoid arthritis (RA) patients undergoing TKA in hybrid technique with a cementless fixation of the femoral component. Methods: We analysed retrospectively 66 RA patients who underwent 72 TKAs (P.F.C. Sigma®). Mean follow-up time was 124 ± 41 months. To evaluate postoperative clinical outcome, knee injury and osteoarthritis outcome score (KOOS) and Oxford knee score (OKS) were assessed. Kaplan–Meier analysis was used to calculate survivorship. The primary outcome was revision for any reason. Results: Thirty-four patients (36 knees) died and two patients (2 knees) were lost to follow-up. Three patients (four knees) did not agree to participate. Twenty-seven patients (30 knees) were available for assessing clinical scores. The average scores were 85 ± 14 for KOOS and 34 ± 10 for OKS. In three patients (three knees), revision was necessary, including restricted range of motion (n = 1), instability (n = 1), and infection (n = 1). There were no cases of loosening in this cohort study. The survival rates were 100% at 5 years, 97.1% at 10 years (95% CI 89.0–99.2%) and 95.6% at 15 years (95% CI 86.9–98.5%). Conclusions: This study confirms that excellent clinical results and a good 10-year survivorship can be obtained with hybrid fixation technique in TKA in the unique population of RA patients.

OBJECTIVE Thrombospondin-1 (TSP-1), a trimeric glycoprotein, is involved in cell-matrix interactions of various tissues, particularly in cartilage. Biochemical analyses show expression of TSP-1 in human cartilage, but its cellular source as well as the presence of its main surface receptors CD36 and CD51 in normal and osteoarthritic cartilage remain unknown. Therefore, to localise TSP-1 and its receptors immunohistochemistry and in situ hybridisation were used. METHODS Radioactive in situ hybridisations with an RNA probe that encodes TSP-1 combined with immunostaining were carried out to investigate the expression patterns of TSP-1, CD36, and CD51 in seven normal and 23 osteoarthritic human cartilage samples. RESULTS In normal cartilage TSP-1 was present mainly in the middle and upper deep zone. RNA expression was predominantly seen over chondrocytes of the middle zone. CD36 was found in chondrocytes of the superficial and upper middle zone. In mild and moderate osteoarthritic cartilage an increased number of TSP-1 expressing chondrocytes were seen and an increased pericellular staining close to the surface. In severe osteoarthritic cartilage a decrease in the number of TSP-1 synthesising chondrocytes and a strong reduction in matrix staining were observed. Most of these severe osteoarthritic samples showed a strongly enhanced number of CD36 positive chondrocytes. CONCLUSION The cellular source of TSP-1 in normal cartilage is mainly mid-zone chondrocytes, which also express CD36. In early osteoarthritic cartilage lesions an increase of TSP-1 was seen, whereas reduced TSP-1 synthesis is paralleled by a strong decrease in TSP-1 protein staining in severe osteoarthritis. Furthermore, in severe osteoarthritic cartilage the number of CD36 immunostained chondrocytes is significantly increased.

The aim of the study was to explore the possible role of Trefoil Factor Family peptide 3 (TFF3) for skeletal repair. The expression of TFF3 was analyzed in human joint tissues as well as in a murine bone fracture model. Serum levels of TFF3 following a defined skeletal trauma in humans were determined by ELISA. The mRNA expression of TFF3 was analyzed under normoxia and hypoxia. Expression analysis after stimulation of human mesenchymal progenitor cells (MPCs) with TFF3 was performed by RT2 Profiler PCR Array. The effect of recombinant human (rh)TFF3 on MPCs was analysed by different migration and chemotaxis assays. The effect on cell motility was also visualized by fluorescence staining of F-Actin. TFF3 was absent in human articular cartilage, but strongly expressed in the subchondral bone and periosteum of adult joints. Strong TFF3 immunoreactivity was also detected in murine fracture callus. Serum levels of TFF3 were significantly increased after skeletal trauma in humans. Expression analysis demonstrated that rhTFF3 significantly decreased mRNA of ROCK1. Wound healing assays showed increased cell migration of MPCs by rhTFF3. The F-Actin cytoskeleton was markedly influenced by rhTFF3. Cell proliferation was not increased by rhTFF3. The data demonstrate elevated expression of TFF3 after skeletal trauma. The stimulatory effects on cell motility and migration of MPCs suggest a role of TFF3 in skeletal repair.

Introduction Limited weight bearing of the lower extremity is a commonly applied procedure in orthopedic rehabilitation following trauma surgery and joint replacement. The compliance of patients with limited weight bearing after cementless total hip arthroplasty has not yet been surveyed using sensor-loaded insoles. The objective of this study was to investigate foot loadings in patients after THA under the assumption of limited weight bearing. Methods Peak pressures for the hindfoot, midfoot and forefoot were obtained from 14 patients (10 women, 4 men, age 63 ± 12 years, height 172 ± 9 cm, weight 92 ± 20 kg, BMI 31 ± 6 kg/m 2 ) by means of dynamic pedobarography, with full weight bearing preoperatively (baseline) and at 8–10 days after cementless total hip arthroplasty, walking again on even floor, and also walking upstairs and downstairs with a restriction of weight bearing to 10 % body weight, taught by an experienced physiotherapist with a bathroom scale. Results Foot loadings with limited weight bearing on even floor remained up to 88 % from full weight bearing preoperatively. Walking upstairs and downstairs under the same condition was approximately equal to a bisection of peak pressures from full weight bearing. Conclusions Patients following cementless do not comply with limited weight bearing when they are trained by the use of a bathroom scale.

We have previously shown that functional inactivation of hypoxia-inducible factor-1α (HIF-1α) in growth-plate chondrocytes will dramatically inhibit anaerobic energy generation and matrix synthesis. Using immunohistochemistry, we have now analyzed the spatial distribution of HIF-1α and its target genes in normal cartilage and in cartilage from knee joints with osteoarthritis. We detected HIF-1α and its target genes in both types of cartilage. In cartilage from joints with osteoarthritis, the number of HIF-1α-, Glut-1-, and PGK-1-stained chondrocytes increased with the severity of osteoarthritis. Activated matrix synthesis and strongly decreased oxygen levels are hallmarks of osteoarthritic cartilage. Thus, we assume that chondrocytes are depending on the adaptive functions of HIF-1α in order to maintain ATP levels and thereby matrix synthesis during the course of osteoarthritis.

Type-VI collagen is an integral part of the extracellular cartilage matrix. However, the exact amounts of type-VI collagen in normal and osteoarthritic human cartilage still are not known. In this study, we describe an inhibition enzyme-linked immunosorbent assay that was developed to quantitate type-VI collagen epitopes found in guanidinium chloride extracts from normal and osteoarthritic human cartilage. In 31 cartilage samples from various localizations of healthy adult human knees, type-VI collagen epitopes accounted for approximately 0.40% of the total collagen content. Interestingly, type-VI collagen epitopes increased about 4-fold in osteoarthritic cartilage. A statistically significant increase of type-VI collagen epitopes was found during early stages of the disease, with only a superficial roughening of the cartilage surface and a loss of proteoglycans. Thus, these findings indicate that type-VI collagen is a minor component of normal human articular cartilage and that the amount of type-VI collagen epitopes increases significantly during early stages of osteoarthritis.

To investigate foot loadings in different leg press settings with respect to a possible graduation of weight bearing (WB). Case series. Assessing plantar force values by means of dynamic pedobarography taken place in orthopaedic departments' rehab center. 15 healthy students (9 men and 6 women, age 23 ± 2, weight 75 ± 6 kg) were recruited as participants from the medical faculty. Peak force values from normal gait (referred to as 100%) and single and double leg presses (SLP, DLP) with resistances of 10 kg, 20 kg and 40 kg, obtained with pedobarographic insoles. Performing DLP produced foot loadings (N) of 37 ± 15 with 10 kg, 91 ± 29 with 20 kg and 203 ± 27 with 40 kg, equal to 5%, 12% and 26% of full WB. SLP result in force values of 195 ± 32 with 10 kg, 308 ± 34 with 20 kg and 516 ± 45 with 40 kg, corresponding to 25%, 40% and 67% baseline. Leg press exercises can be performed in accordance with a given limitation of foot loading. Above mentioned conditions allow a graduation from 5% to 67% of full WB. •Leg presses can be performed to modified weight bearing conditions.•Leg press settings allow an adjustment from 5% to 67% of full weight bearing.•Pedobarography seems a suitable method to monitor foot loads during leg presses at 40 kg but is less valid at lower loads.