Dorso-ventral osteophytes of interphalangeal joints correlate with cartilage damage and synovial inflammation in hand osteoarthritis: a histological/radiographical study.

OBJECTIVE: To detect dorsally located osteophytes (OP) on lateral x-ray views and to correlate their presence with the extent of structural joint damage, determined by histologic grading (cartilage damage and synovial inflammation) and radiographic scoring in hand osteoarthritis (HOA). METHODS: Distal interphalangeal (DIP) and proximal interphalangeal (PIP) joints were obtained from post mortem specimens (n = 40). Multiplanar plain x-rays were taken (dorso/palmar (dp) and lateral views). Radiographic OA was determined by the Kellgren and Lawrence classification. Joint samples were prepared for histological analysis and cartilage damage was graded according to the Mankin scoring system. Inflammatory changes of the synovial membrane were scored using the general synovitis score (GSS). Spearman's correlation was applied to examine the relationship between histological and radiographical changes. Differences between groups were determined by Mann-Whitney test. RESULTS: Bony proliferations that were only detectable on lateral views but reminiscent of OPs on dp images were termed dorso-ventral osteophytes (dvOPs). All joints displaying dvOPs were classified as OA and the presence of dvOPs in DIP and PIP joints correlated with the extent of histological and radiographic joint damage, as well as with patient age. Joint damage in osteoarthritic DIP and PIP joints without any dvOPs was less severe compared to joints with dvOPs. Synovial inflammation was mainly present in joints displaying dvOPs and correlated with joint damage. CONCLUSION: dvOPs are associated with increasing structural alterations in DIP and PIP joints and can be seen as markers of advanced joint damage. Detecting dvOPs can facilitate the diagnosis process and improve damage estimation in HOA.

Hand X-ray examination in two planes is not required for radiographic assessment of hand osteoarthritis.

AIMS: Radiographic imaging is essential in the diagnosis of hand osteoarthritis (HOA); however, it is unknown whether a multiplanar examination would add essential information to dorso-palmar (dp) views alone. This study evaluated whether an additional radiographic view would aid clinicians in the diagnostic process of HOA. METHODS: The dp radiographs of both hands from 159 HOA patients were assessed according to the scores described by Kellgren and Lawrence (K/L). In oblique view images, structures similar to classic ostophytes (OPs) were found, namely bony proliferations on the dorsal and/or ventral margins of joints, and were documented as dorsal/ventral OPs (dvOPs). Function and pain were assessed by applying standardised read-out systems. Logistic regression analysis and Mann-Whitney tests were implemented. RESULTS: The presence of dvOPs was associated with the degree of joint damage; however, dp views were sufficient to estimate radiographic changes. Only a few joints showed dvOPs as the only structural alteration; nevertheless, in almost all cases, classical radiographic OA changes were found in dp views of other joints of the same or the contralateral hand. The presence of dvOPs did not affect joint function or pain according to established scores, but was associated with radiographic progression in distal interphalangeal joints. CONCLUSION: This is the first study to confirm that additional radiographic planes, oblique/lateral views, are not necessary in the diagnostic process in HOA in daily clinical practice. Nevertheless, the presence of dvOPs reflect more severe joint damage and is associated with radiographic progression in HOA; hence, oblique/lateral views could be a useful tool for academic purposes.

Interphalangeal Osteoarthritis Radiographic Simplified (iOARS) score: a radiographic method to detect osteoarthritis of the interphalangeal finger joints based on its histopathological alterations.

OBJECTIVE: To develop a radiographic score for assessment of hand osteoarthritis (OA) that is based on histopathological alterations of the distal (DIP) and proximal (PIP) interphalangeal joints. METHODS: DIP and PIP joints were obtained from corpses (n=40). Plain radiographies of these joints were taken. Joint samples were prepared for histological analysis; cartilage damage was graded according to the Mankin scoring system. A 2×2 Fisher's exact test was applied to define those radiographic features most likely to be associated with histological alterations. Receiver operating characteristic curves were analysed to determine radiographic thresholds. Intraclass correlation coefficients (ICC) estimated intra- and inter-reader variability. Spearman's correlation was applied to examine the relationship between our score and histopathological changes. Differences between groups were determined by a Student's t test. RESULTS: The Interphalangeal Osteoarthritis Radiographic Simplified (iOARS) score is presented. The score is based on histopathological changes of DIP and PIP joints and follows a simple dichotomy whether OA is present or not. The iOARS score relies on three equally ranked radiographic features (osteophytes, joint space narrowing and subchondral sclerosis). For both DIP and PIP joints, the presence of one x-ray features reflects interphalangeal OA. Sensitivity and specificity for DIP joints were 92.3% and 90.9%, respectively, and 75% and 100% for PIP joints. All readers were able to reproduce their own readings in DIP and PIP joints after 4 weeks. The overall agreement between the three readers was good; ICCs ranged from 0.945 to 0.586. Additionally, outcomes of the iOARS score in a hand OA cohort revealed a higher prevalence of interphalangeal joint OA compared with the Kellgren and Lawrence score. CONCLUSIONS: The iOARS score is uniquely based on histopathological alterations of the interphalangeal joints in order to reliably determine OA of the DIP and PIP joints radiographically. Its high specificity and sensitivity together with the dichotomous approach renders the iOARS score reliable, fast to perform and easy to apply. This tool may not only be valuable in daily clinical practice but also in clinical and epidemiological trials.

Histopathological correlation supports the use of x-rays in the diagnosis of hand osteoarthritis.

OBJECTIVE: To correlate histopathological and radiographic features of distal and proximal interphalangeal (DIP and PIP) joints in order to test whether the use of an x-ray examination would be beneficial to the classification/diagnosis process of hand osteoarthritis (OA). METHODS: DIP and PIP joints were obtained from post mortem specimens (n=40). Plain x-rays of the DIP and PIP joints were taken and radiographic OA was determined by the Kellgren and Lawrence classification. Individual radiographic features were scored according to the method described by Altman. Joint samples were prepared for histological analysis; cartilage damage was graded according to the Mankin scoring system. Spearman's correlation was applied to examine the relationship between histological and radiographical changes. Differences between groups (bony swelling vs no bony swelling) were determined by Student t test. RESULTS: A highly significant correlation was found between histological (Mankin score) and radiographic (Kellgren/Lawrence score) changes in the investigated DIP (r(s)=0.87, p<0.0001) and PIP (r(s)=0.79, p<0.0001) joints. A subgroup of patients (37.5% for DIP and 18.8% for PIP joints) showed advanced radiographic changes (Kellgren/Lawrence score ≥2) in joints without clinical bony swelling. Histologically, the mean Mankin scores accounted for 11±1.66 for DIP and 9.67±2.4 for PIP joints. CONCLUSION: On the basis of histopathological changes of DIP and PIP joints, this investigation demonstrates the validity of x-ray examinations and supports the use of plain radiography in the diagnosis of hand OA and in the classification of hand OA in clinical trials.

Differentially regulated expression of growth differentiation factor 5 and bone morphogenetic protein 7 in articular cartilage and synovium in murine chronic arthritis: potential importance for cartilage breakdown and synovial hypertrophy.

OBJECTIVE: To examine whether the endogenous expression of growth differentiation factor 5 (GDF-5) and bone morphogenetic protein 7 (BMP-7) is altered in the cartilage and synovium of human tumor necrosis factor alpha (TNFalpha)-transgenic (hTNFtg) mice with chronic arthritis, and to investigate the response of hTNFtg chondrocytes as well as fibroblast-like synoviocytes (FLS) to these morphogens in vitro. METHODS: Analyses were performed in hTNFtg mice with chronic destructive arthritis and in wild-type (WT) mice as controls. Expression of GDF-5 and BMP-7 in the articular cartilage and synovium was examined by real-time polymerase chain reaction and immunohistochemistry. Human TNFtg cartilage explants, chondrocytes, and FLS monolayer cultures were assessed for basal matrix biosynthesis as well as growth factor responsiveness, using (35)S-sulfate incorporation assays. In addition, the DNA content/cell proliferation rate was measured. RESULTS: The expression of GDF-5 and BMP-7 was decreased in articular cartilage from hTNFtg mice, whereas expression of both morphogens was increased in arthritic synovium from hTNFtg mice, as compared with the levels in WT controls. Isotope incorporation revealed a marked reduction of matrix synthesis in hTNFtg cartilage as well as a decrease in responsiveness to GDF-5 and BMP-7. The DNA content did not change in arthritic cartilage as compared with WT cartilage. In hTNFtg FLS, growth factor stimulation increased the rate of cell proliferation and the production of extracellular matrix. CONCLUSION: In this murine model of TNFalpha-mediated arthritis, the expression of GDF-5 and BMP-7 is regulated differentially in articular cartilage and synovium. In articular cartilage, the down-regulation of GDF-5 and BMP-7, which function to maintain matrix integrity, could potentially compromise tissue repair, whereas in synovium, the increased expression of GDF-5 and BMP-7 might contribute to synovial hypertrophy.

Increased expression of discoidin domain receptor 2 is linked to the degree of cartilage damage in human knee joints: a potential role in osteoarthritis pathogenesis.

OBJECTIVE: To investigate the relationship between increased discoidin domain receptor 2 (DDR-2) expression and cartilage damage in osteoarthritis (OA). METHODS: Full-thickness cartilage tissue samples from 16 human knee joints were obtained and the grade of cartilage damage was evaluated according to the Mankin scale. Expression of DDR-2, matrix metalloproteinase 13 (MMP-13), and MMP-derived type II collagen fragments was visualized immunohistochemically. Moreover, upon stimulation with either type II collagen or gelatin, levels of DDR-2 and MMP-13 messenger RNA (mRNA) in primary human articular chondrocytes were assessed by real-time polymerase chain reaction. RESULTS: Immunohistochemical analysis showed an increase in DDR-2 expression in human articular cartilage, which was correlated with the degree of tissue damage. In parallel, the extent of MMP-13 and type II collagen breakdown products was elevated as a function of increased DDR-2 expression and cartilage damage. Furthermore, in vitro experiments revealed an up-regulation of both DDR-2 and MMP-13 mRNA in human articular chondrocytes after stimulation with type II collagen. CONCLUSION: Our data indicate that 3 factors, DDR-2 expression, MMP-13 expression, and the degree of cartilage damage, are linked, such that DDR-2 promotes tissue catabolism, and tissue degradation promotes DDR-2 up-regulation and activation. Thus, the perpetuation of DDR-2 expression and activation can be seen as a vicious circle that ultimately leads to cartilage destruction in OA.

Age-dependent expression of VEGF isoforms and receptors in the rabbit anterior cruciate ligament.

Vascular endothelial growth factor (VEGF) gene gives rise to several distinct isoforms of VEGF. Those isoforms differ in biochemical and biological properties, and it has been reported that their expression patterns are tissue and age specific as well. We investigated the expression levels of VEGF isoforms (VEGF121, VEGF165, VEGF183, VEGF189) and its receptors (VEGFR-1, flt-1 and VEGFR-2, flk-1/KDR) in the anterior cruciate ligament (ACL) of 2- to 3-week-, 2-month-, and 18-month-old New Zealand White rabbits using Sybr green Real-Time RT-PCR. VEGF isoforms and both receptors were expressed in the ACL at all investigated ages. VEGF121 was found to be the most abundant isoform at the ages under investigation, followed by VEGF165, VEGF189 and VEGF183. All isoforms showed decreased expression levels with age, however the larger membrane bound isoforms, VEGF183 and VEGF189, showed the most striking age-associated decrease in expression level. VEGFR-1 expression levels increased with age, while the expression level of VEGFR-2 expression was highest at 2-3 weeks and was significantly lower at 2 and 18 months of age. Distinct age-associated differences in the expression level of VEGF isoforms as well as their receptors suggest differential physiological functions during development, maturation and ageing of the ACL.

Impairment of chondrocyte biosynthetic activity by exposure to 3-tesla high-field magnetic resonance imaging is temporary.

The influence of magnetic resonance imaging (MRI) devices at high field strengths on living tissues is unknown. We investigated the effects of a 3-tesla electromagnetic field (EMF) on the biosynthetic activity of bovine articular cartilage. Bovine articular cartilage was obtained from juvenile and adult animals. Whole joints or cartilage explants were subjected to a pulsed 3-tesla EMF; controls were left unexposed. Synthesis of sulfated glycosaminoglycans (sGAGs) was measured by using [35S]sulfate incorporation; mRNA encoding the cartilage markers aggrecan and type II collagen, as well as IL-1beta, were analyzed by RT-PCR. Furthermore, effects of the 3-tesla EMF were determined over the course of time directly after exposure (day 0) and at days 3 and 6. In addition, the influence of a 1.5-tesla EMF on cartilage sGAG synthesis was evaluated. Chondrocyte cell death was assessed by staining with Annexin V and TdT-mediated dUTP nick end labelling (TUNEL). Exposure to the EMF resulted in a significant decrease in cartilage macromolecule synthesis. Gene expression of both aggrecan and IL-1beta, but not of collagen type II, was reduced in comparison with controls. Staining with Annexin V and TUNEL revealed no evidence of cell death. Interestingly, chondrocytes regained their biosynthetic activity within 3 days after exposure, as shown by proteoglycan synthesis rate and mRNA expression levels. Cartilage samples exposed to a 1.5-tesla EMF remained unaffected. Although MRI devices with a field strength of more than 1.5 T provide a better signal-to-noise ratio and thereby higher spatial resolution, their high field strength impairs the biosynthetic activity of articular chondrocytes in vitro. Although this decrease in biosynthetic activity seems to be transient, articular cartilage exposed to high-energy EMF may become vulnerable to damage.