Disease Of Synovial Joints Research Articles

Interactive Cytokine Regulation of Synoviocyte Lubricant Secretion

Cytokine regulation of synovial fluid (SF) lubricants, hyaluronan (HA), and proteoglycan 4 (PRG4) is important in health, injury, and disease of synovial joints, and may also provide powerful regulation of lubricant secretion in bioreactors for articulating tissues. This study assessed lubricant secretion rates by human synoviocytes and the molecular weight (MW) of secreted lubricants in response to interleukin (IL)-1beta, IL-17, IL-32, transforming growth factor-beta 1 (TGF-beta1), and tumor necrosis factor-alpha (TNF-alpha), applied individually and in all combinations. Lubricant secretion rates were assessed using ELISA and binding assays, and lubricant MW was assessed using gel electrophoresis and Western blotting. HA secretion rates were increased approximately 40-fold by IL-1beta, and increased synergistically to approximately 80-fold by the combination of IL-1beta + TGF-beta1 or TNF-alpha + IL-17. PRG4 secretion rates were increased approximately 80-fold by TGF-beta1, and this effect was counterbalanced by IL-1beta and TNF-alpha. HA MW was predominantly <1 MDa for controls and individual cytokine stimulation, but was concentrated at >3 MDa after stimulation by IL-1beta + TGF-beta1 + TNF-alpha to resemble the distribution in human SF. PRG4 MW was unaffected by cytokines and similar to that in human SF. These results contribute to an understanding of the relationship between SF cytokine and lubricant content in health, injury, and disease, and provide approaches for using cytokines to modulate lubricant secretion rates and MW to help achieve desired lubricant composition of fluid in bioreactors.

Interleukin‐1β–Induced Extracellular Matrix Degradation and Glycosaminoglycan Release Is Inhibited by Curcumin in an Explant Model of Cartilage Inflammation

Osteoarthritis (OA) is a degenerative and inflammatory disease of synovial joints that is characterized by the loss of articular cartilage, for which there is increasing interest in natural remedies. Curcumin (diferuloylmethane) is the main polyphenol in the spice turmeric, derived from rhizomes of the plant Curcuma longa. Curcumin has potent chemopreventive properties and has been shown to inhibit nuclear factor kappaB-mediated inflammatory signaling in many cell types, including chondrocytes. In this study, normal articular cartilage was harvested from metacarpophalangeal and metatarsophalangeal joints of eight horses, euthanized for reasons other than research purposes, to establish an explant model mimicking the inflammatory events that occur in OA. Initially, cartilage explants (N= 8) were stimulated with increasing concentrations of the proinflammatory cytokine IL-1beta to select effective doses for inducing cartilage degeneration in the explant model. Separate cartilage explants were then cotreated with IL-1beta at either 10 ng/mL (n= 3) or 25 ng/mL (n= 3) and curcumin (0.1 micromol/L, 0.5 micromol/L, 1 micromol/L, 10 micromol/L, and 100 micromol/L). After 5 days, the percentage of glycosaminoglycan (GAG) release from the explants was assessed using a dimethylmethylene blue colorimetric assay. Curcumin (100 micromol/L) significantly reduced IL-1beta-stimulated GAG release in the explants by an average of 20% at 10 ng/mL and 27% at 25 ng/mL back to unstimulated control levels (P < 0.001). Our results suggest that this explant model effectively simulates the proinflammatory cytokine-mediated release of articular cartilage components seen in OA. Furthermore, the evidence suggests that the inflammatory cartilage explant model is useful for studying the effects of curcumin on inflammatory pathways and gene expression in IL-1beta-stimulated chondrocytes.

The Death Receptor 3–TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints that is associated with cartilage and bone destruction. Death Receptor 3 (DR3), a tumor necrosis factor (TNF) receptor superfamily member, has recently been associated with the pathogenesis of RA. We demonstrate that absence of DR3 confers resistance to the development of adverse bone pathology in experimental antigen-induced arthritis (AIA). DR3ko mice exhibited a reduction in all histopathological hallmarks of AIA but, in particular, failed to develop subchondral bone erosions and were completely protected from this characteristic of AIA. In contrast, TNF-like protein 1A (TL1A), the ligand for DR3, exacerbated disease in a dose- and DR3-dependent fashion. Analysis of osteoclast number within AIA joint revealed a reduction in areas susceptible to bone erosion in DR3ko mice, whereas in vitro osteoclastogenesis assays showed that TL1A could directly promote osteoclastogenesis in mouse and man. Treatment with antagonistic anti-TL1A mAb protected animals in a systemic model of RA disease collagen-induced arthritis. We therefore conclude that the DR3–TL1A pathway regulates joint destruction in two murine models of arthritis and represents a potential novel target for therapeutic intervention in inflammatory joint disease.

Synvisc®in knee osteoarthritis

Osteoarthritis (OA) is a chronic degenerative disease of synovial joints that is characterized by the deterioration of hyaluronan and other constituents of hyaline cartilage, resulting in intermittent pain, swelling, inflammation and varying degrees of functional loss. Viscosupplementation is one of the treatment options for OA-related pain and has been used successfully for several years. Hylan GF-20 (Synvisc®) is a viscosupplement composed of two cross-linked hylan polymers that form a high-molecular-weight hyaluronan compound. Numerous systemic reviews, clinical trials and meta-analyses have established the efficacy of Synvisc for OA knee pain. In comparison with multiple control groups, multiple active comparators and other hyaluronic acid treatments, it has provided equal or better pain relief. Synvisc is effective in repeat treatment cycles and in delaying total knee replacement. Overall, Synvisc has proved efficacious in the treatment of knee OA and has a well-established track record of safety, ef...

Subchondral thickness does not vary with cartilage degeneration on the metatarsal.

Osteoarthritis is a disease of synovial joints that involves articular cartilage breakdown with accompanying bone changes, including subchondral sclerosis and osteophytosis. However, conflicting data have been reported concerning the cause-and-effect relationship, if any, between these changes. The authors studied the subchondral plate (subchondral bone plus calcified cartilage) in relation to the degree of articular cartilage degeneration on the distal articular surface of the first metatarsal, a region prone to osteoarthritis. No correlation was found between subchondral plate thickness or porosity and the degree of cartilage degeneration in the study sample of 96 metatarsals. Owing to the suggestion that initiation of cartilage fibrillation may be a result of steep stiffness gradients in the subchondral bone, the ratios of subchondral plate thickness in adjacent regions of the metatarsal head were examined in detail, but no correlation was found with subchondral degeneration. Thus increases in subchondral bone thickness are not associated with increases in cartilage degeneration on the first metatarsal, which may imply that subchondral bone changes do not cause osteoarthritis in this joint.

Synovial joint disease in wild cetaceans.

During necropsy of cetaceans stranded or accidentally net-captured along the western coast of the Gulf of Mexico from 1991 to 1996, we found 13 of 59 (22%) animals had abnormalities of the atlanto-occipital and/or humeroscapular joints, the synovial joints. A few cases demonstrated mild roughening of the articular cartilage, while the majority exhibited complete erosion with thickened synovium and bony proliferation. The lesions resulted in ankylosis of both joints in one animal. In humans and terrestrial mammals, synovial joint diseases are known to be debilitating. Cetaceans depend on neck and flipper movement for locomotion, feeding, avoiding danger, and reaching the water's surface for breathing. Therefore, synovial joint disease may be significant mortality factor in these marine animals.

Expression and Activity of Articular Cartilage Hyaluronidases

The glycosaminoglycan hyaluronan is an important component of the extracellular matrix of articular cartilage, contributing to both the structural and functional integrity of this highly specialized tissue. Hyaluronan is known to be synthesized and turned over by the resident chondrocytes, although the mechanisms involved in hyaluronan degradation are not precisely defined. Recently, the cDNA sequences of extracellular hyaluronidases present on spermatazoa and in human serum have been reported, and we have utilized these data to investigate the expression and activity of these and/or related enzymes by articular cartilage chondrocytes. By using “gene-homology” RT-PCR techniques, three hyaluronidase isozymes were found to be expressed by chondrocytes, and hyaluronidase activity was detected in cell membrane extracts and conditioned media from chondrocyte monolayer cultures following acidification to pH 4.5 or pH 3.7. In addition, the levels of mRNA for two of the chondrocyte hyaluronidases were upregulated by IL-1 and TNF stimulation, thereby implicating cartilage-derived hyaluronidase activity as a factor contributing to cytokine-induced extracellular matrix degradation during synovial joint disease.

Splicing patterns of fibronectin mRNA from normal and osteoarthritic human articular cartilage

Fibronectin, a large extracellular glycoprotein, mediates the interaction of cells with the extracellular matrix. Heterogeneity in the structure of fibronectin is largely due to the alternative splicing of three exons (IIIB, IIIA and V) during processing of the fibronectin primary transcript. Osteoarthritis, a degenerative disease of synovial joints, is characterized by a progressive loss of the articular cartilage eventually resulting in pain and loss of joint function. In contrast to the loss of most cartilage matrix proteins accompanying this process, osteoarthritic cartilage contains more fibronectin than disease-free cartilage. We examined the splicing patterns of fibronectin mRNA from adult human articular cartilage of normal and osteoarthritic joints by RNase protection (exon IIIA and exon IIIB) and reversed transcription-polymerase chain reaction (exon V) assays to determine whether or not the increased fibronectin content in osteoarthritic cartilage is also associated with differences in the splicing patterns of these three alternatively spliced exons. The results revealed no gross differences in splicing of these exons between the fibronectin mRNA isolated from adult human articular normal and osteoarthritic cartilage. Thus alterations in the structure of cartilage fibronectin do not appear to correlate with the increased level of fibronectin protein associated with osteoarthritis.

Calcium pyrophosphate dihydrate crystal deposition disease: a review of the literature and a light and electron microscopic study of a case of the temporomandibular joint with numerous intracellular crystals in the chondrocytes

The pathogenesis of calcium pyrophosphate dihydrate (CPPD) crystal deposition disease of synovial joints is still unclear, although overproduction of extracellular pyrophosphate (PPi) is thought to play a key role. We studied the light and electron microscopic appearances of a case of CPPD crystal deposition disease of the temporomandibular joint (TMJ) in search of new clues for its pathogenesis. Light microscopic examination of CPPD-containing material from the joint space revealed cartilaginous nodules with various degrees of crystallization. Transmission electron microscopic examination revealed numerous extra- as well as intracellular crystals and crystal shaped spaces in the chondrocytes. Other striking ultrastructural features of the chondrocytes included the presence of many mitochondria, frequently containing crystalline material, and the presence of highly dilated rough endoplasmic reticulum and large glycogen islands. The presence of intramitochondrial crystals may hypothetically imply a derangement in mitochondrial adenosine triphosphate or PPi metabolism. The finding of intracellular CPPD crystals in chondrocytes points to the existence of an intracellular pathway of CPPD crystal formation in CPPD crystal deposition disease of the TMJ and possibly in CPPD crystal deposition disease in general.