Current Rheumatology Reviews - Volume 2, Issue 1, 2006

Hepatocyte Growth Factor (HGF) is a multifunctional growth factor which, like its receptor c-Met, is widely expressed in osteoarticular tissues. HGF has profound effects on cell motility and differentiation and tissue morphogenesis and angiogenesis. HGF plays an important role in normal bone and cartilage turnover. Changes in HGF/c-Met have also been linked to pathophysiological changes in several bone and joint disorders. HGF has been implicated in the pathogenesis of inflammatory changes in rheumatoid synovium and in degenerative changes in osteoarthritis. HGF also influences bone remodelling and has significant effects on the proliferation and differentiation of osteoclast precursors, osteoclast activity and survival. A therapeutic role of HGF also has been proposed in the regeneration of osteoarticular tissues.

The protein kinase PKR is a key regulator of stress signalling pathways. We found that the PKR activating protein (PACT) is up-regulated in cartilage at the onset of osteoarthritis. PACT activates PKR in response to various cellular stresses such as TNF-α and IL-1. TNF-α also activates PKR via the sphingolipid second messenger, ceramide. Recent studies have shown that ceramide-induced activation of PKR inhibits protein synthesis as a prelude to cell death. TNF-α and ceramide stimulate cartilage degradation and we have demonstrated a role for PKR in TNF-α and ceramideinduced increases in the expression and activation of degradative enzymes in articular cartilage. The known role of PKR in cytokine-induced signalling pathways, together with our data showing cytokine regulation of PKR in chondrocytes, reveals a novel mechanism of cartilage degradation that may be important in the pathogenesis of arthritis. Elucidation of this pathway may enable more subtle control of cytokine-mediated degradation of cartilage and improve upon the efficacy of anti-TNF treatments in arthritis. This review will summarise the known activities of PKR and provide evidence for the involvement of this signalling pathway in cartilage breakdown.

The efficacy of high molecular weight hyaluronan (HA) in reversing cartilage damage in patients with joint degeneration has not yet been clearly demonstrated, although there is compelling evidence of reduction in parameters of pain. The rationales as to why HA may be beneficial to cartilage structure are diverse and are largely based on studies of in vitro models of cartilage damage. However, there are few studies in these models showing a linkage between effects of HA on cartilage metabolism to an outcome more closely related to osteoarthritis, such as cartilage matrix degradation. Thus, while HA may have a myriad of effects on chondrocytes, perhaps not all of these explain its potential chondroprotective activity. This review discusses selected studies and question whether there is a common explanation for efficacy of HA. It is concluded and proposed that HA may be a weak catabolic mediator that stimulates anabolic processes in cartilage. Thus, the efficacy of HA may be explained by the linkage of catabolic events to subsequent anabolic reparative responses, a newer theme supported by numerous studies.

A fine balance between cartilage matrix synthesis and degradation is critical both for the maintenance of articular cartilage function and skeletal development and growth. Disruption of this balance causes abnormalities in skeletal formation and growth and leads to degenerative cartilage diseases, including osteoarthritis and rheumatoid arthritis. Previous studies from this and other laboratories have indicated that Wnt proteins regulate chondrocyte function and behavior and also play important roles in cartilage development and skeletogenesis, from the initial steps of chondrogenesis to the final steps during which calcified cartilage is replaced by bone. Inhibition of Wnt/β -catenin signaling suppresses chondrocyte maturation and endochondral ossification, while activation both inhibits cartilage matrix synthesis and accumulation and impairs growth plate organization and tissue integrity. We found that activation of Wnt/β - catenin signaling strongly stimulated proteoglycan loss from chondrocyte cultures and cartilage explants while upregulated the expression of genes responsible for cartilage matrix degradation. Furthermore, β-catenin accumulates in chondrocytes located in osteoarthritic articular cartilage in a manner similar to that normally occurring in growth plate hypertrophic chondrocytes, suggesting that Wnt/β -catenin signaling is activated in regions where active matrix degradation occurs; thus, Wnt/β -catenin signaling may be a common pathway regulating matrix disruption during endochondral ossification and pathological degeneration of cartilage.

Evaluation of differentially regulated genes is essential for the development of novel therapeutic approaches in multifactorial diseases such as rheumatoid arthritis (RA). The analysis of the pathophysiology of RA requires also a functional understanding of the interactions between different cell types, the cell matrix, intracellular signaling pathways, often also called 'functional genomics', as well as between the different tissues in the joint such as cartilage, bone, adipose tissue, and the synovium. In addition, the identification of disease- or treatment-specific genes has become an important tool in arthritis research to determine novel molecular markers for diagnosis and monitoring of RA, and to elucidate the exact mode of operation and the potential target molecules for therapeutic intervention. Current approaches to analyze gene expression in arthritis are based on RNA isolated from cultured synovial cells or from synovial tissues and biopsies. Other approaches are directed to cultured cells such as RA synovial fibroblasts, one of the key players in inflammation and cartilage destruction, chondrocytes, macrophages or lymphocytes to characterize molecular changes and pathomechanisms in the RA synovium, especially at sites of adhesion and invasion of the synovium into the adjacent cartilage and bone. In this review, different methods to analyze gene expression of cells and tissues from patients with arthritides ranging from RNA fingerprinting to cDNA array are presented and discussed. In addition, a special focus is addressing the pitfalls resulting in over- or misinterpretation of the data obtained by these sensitive techniques.

Rheumatoid arthritis (RA) is characterized by hyperplasia of synovial lining cells, consisting of macrophagelike type A synoviocytes and fibroblast-like type B synoviocytes. Type A synoviocytes, also called intimal macrophages, have been found to be derived from monocyte precursors in the bone marrow. Accordingly, the spontaneous generation of CD14+ cells from bone marrow CD14- progenitor cells is accelerated in RA, resulting in the facilitated entry of such CD14+ cells into the synovium. Whereas type B synoviocytes, also called fibroblast-like synoviocytes, are thought to arise from the sublining tissue or other support structures of the joint, they might be also derived from bone marrow progenitor cells. Thus, RA bone marrow CD34+ cells show abnormal responses to TNF-β , resulting in their accelerated differentiation into fibroblast-like cells producing MMP-1. On the other hand, persistent neovascularization is crucial for continuous synovial proliferation through delivery of nutrients and recruitment of inflammatory cells. In this regard, RA bone marrow CD34+ cells differentiate into endothelial cells much more effectively than control subjects, suggesting that bone marrow CD34+ cells might play a role in the synovial hyperplasia in RA through mobilization of endothelial progenitor cells that contribute to vasculogenesis. Taken together, these results support the hypothesis that the bone marrow, rather than the synovium, might be the primary-lesion site of RA.

Ankylosing spondylitis (AS) is a potentially disabling rheumatic disease for which no curative treatment has yet been discovered. An extensive computer-based and manual search was undertaken to evaluate the role of microbes in the pathogenesis of AS. All together 147 papers were scrutinised. A total of 24 studies carried out on 1330 AS patients and 1191 healthy controls involving 15 different countries showed significantly elevated Klebsiella antibodies in AS patients when compared to controls. Molecular analysis has shown that Klebsiella microbes possess antigens, which cross-react with self-antigens, such as HLA-B27 and spinal collagens. Diagnostic criteria have been developed in which a person who is HLA-B27 positive and has clinical and laboratory evidence of an inflammatory backache for at least three months is proposed to have pre-AS. A specific elevation of anti- Klebsiella antibodies would confirm the diagnosis. A proposal for an early treatment using anti-Klebsiella measures is suggested. So far, apart from Klebsiella no other microbes have been shown to have a link with the development of AS. It is suggested that identifying and treating patients with Klebsiella reactive arthritis/pre-AS could involve the use of anti- Klebsiella measures, such as antibiotics and low starch diet together with immunosuppressive drugs in an endeavour to prevent the irreversible sequelae of established AS.

Chronic pain has manifested itself as an independent disease. Different molecules acting in nociceptive pathways in the periphery and the nervous system are currently under investigation. Recently the multifunctional protein DREAM (D ownstream Regulatory Element Antagonist Modulator)/calsenilin/KChIP3 has been implicated to play a role in the mechanisms of pain modulation and the hypothesis "No DREAM - No pain" was raised. In addition to the binding to DRE (Downstream Regulatory Element) sequences, DREAM/calsenilin/KChIP3 was shown to interact with presenilin, a protein thought to be a key molecule in Alzheimer's disease, and Kv4alpha-subunits assembling potassium channels. DREAM/calsenilin/KChIP3 has been described as a Ca2+-dependent transcriptional repressor, which is targeted to the regulatory DNA sequence of the prodynorphin gene. By actively suppressing gene expression of the endogenous opioid receptor ligand dynorphin, DREAM/calsenilin/KChIP3 is modulating the kappa opioid receptor system, which mediates analgesia. DREAM knockout mice showed elevated levels of dynorphin and consequently displayed attenuated chemical induced and inflammatory pain. The data derived from the DREAM knock-out model led to the identification of a novel target in chronic pain management. In this review we focus on DREAM/calsenilin/KChIP3 and its role in pain relief.

Patients with Systemic Sclerosis [SSc] present great variability in the extent of skin sclerosis, internal organ involvement and prognosis. These aspects have long prompted clinical investigators to differentiate SSc into subsets. The most widely used subsetting schema was proposed by Carwile LeRoy et al. in 1988. The schema differentiates two main subgroups (i.e., limited cutaneous SSc -lcSSc- and diffuse cutaneous SSc -dcSSc-) characterized by different extent of skin sclerosis, autoantibody profile and pattern of internal organ involvement. This schema, however, is based on a Delphy technique (i.e. a consensus among experts). The other available schema, which differentiates three subsets according to skin sclerosis (i.e. lc-SSc characterized by sclerodactyly alone, intermediate cutaneous SSc-ic-SSc where the limbs are also involved, and dc-SSc with trunk skin sclerosis) has been demonstrated to have a greater prognostic power, but lacks any reference to other prognostically relevant items . A prospective multicenter study devoted to improve the three subsetting schema by adding such items could help the clinical investigator to better differentiate SSc subsets.

Peripheral nervous system dysfunction is well documented in Sjogren's syndrome (SS), whereas central nervous system involvement is a matter of significant controversy. On the other hand, autonomic nervous system (ANS) dysfunction is not even mentioned in extensive reviews of the disease in classic rheumatology textbooks. Despite isolated reports, attention to such involvement in the rheumatologic literature has only been noted over the last six years, following a controlled prospective study that suggested significant autonomic cardiovascular neuropathy in these patients. Since then, few studies, on relatively small numbers of Sjögren's patients, have yielded conflicting results, including two that claim no abnormality in autonomic nervous system function. A variety of factors may be blamed for these discrepancies, including bias on patient selection but mainly differences in employed methodology, i.e. conventional cardiovascular reflex tests and baroreflex sensitivity vs 24 hour heart rate variability. In any case, besides isolated case reports describing severe autonomic dysfunction, usually manifested by postural hypotension, the majority of studies that indicate the presence of ANS abnormalities in SS, have detected that only by applying objective tests and specific questionnaires. On the other hand, ANS dysfunction, implying defective innervation of exocrine glands, and the presence of muscarinic receptor antibodies have been blamed, partially at least, for the decreased secretory function of exocrine glands in this disease. More importantly, ANS dysfunction has been reported to result in increased mortality in diabetics, post myocardial infarction patients and the elderly. If such a possibility exists for patients with SS, the need for prospective, controlled and long follow up studies on large cohorts is imperative.

The deposition of calcium-containing crystals in articular tissues is probably an under-recognized event. Clinical observations indicate that exaggerated and uniquely distributed cartilage degeneration is associated with these deposits. Perhaps the most compelling argument favoring a role for crystals in Osteoarthritis (OA) stems from their in vitro effects on articular tissues. Therapeutic options are limited and of compromised value for controlling and/or eliminating calcium crystal salt diseases. This review highlights past and present studies related to phosphocitrate (PC), a relatively unheralded compound with an ability to inhibit crystal nucleation, growth and aggregation of calcium salts, including basic calcium phosphate (a term including carbonate-substitute apatite, octacalcium phosphate, and tricalcium phosphate) and calcium pyrophosphate dihydrate. In addition, cell culture studies reveal that specific calcium phosphateinduced cellular events associated with osteoarthritis also are retarded by PC. Interest in the tetra-sodium PC form and the new Calcium/Sodium/PC (CaNaPC) salt has stemmed from their chemical characteristics and biological actions. In two instances, the CaNaPC has displayed superior inhibitory properties to that of the tetra-sodium salt. Using a calcergy animal model, a chemically-induced calcifying skin plaque in rats has been ameliorated while in cell culture studies, strong inhibition of calcium phosphate-DNA co-precipitates induced cell death has been noted. The assessed data indicate that either of the PC salts through their modes of action, could be useful as adjunct therapeutic treatment of crystal associated OA.

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent self-limited febrile episodes. The hallmarks of a typical attack are fever, peritonitis, pleuritis, arthritis and/or erysipelas-like erythema that resolve within hours or days. The disease primarily affects Sephardic Jews, Armenians, Turks and North African Arabs. The frequency of the attacks can vary and the inciting factors are not always clear. Almost half of all patients with FMF have arthritis of the ankle, knee or hip, and there are increasing reports of vasculitic features. The first episode of FMF typically occurs during childhood or adolescence, but the disease may be evident even in infancy. By age 20, approximately 90% of patients have had their first attack. FMF is caused by a defect in the gene that encodes pyrin, a protein that affects the actions of neutrophils and monocytes during the inflammatory response. This "MEFV gene" is located on the short arm of chromosome 16, and 89 MEFV variants have been described to date. The most common MEFV mutations are M694V, M680I, V726A and M694I (all located in exon 10) and E148Q (located in exon 2). Genotype-phenotype correlations in FMF are not yet clear. The most important complication of this illness is development of secondary amyloid A-type amyloidosis. Amyloid fibrils are deposited in the patient's kidneys, gastrointestinal tract, liver, adrenal glands and spleen. Proteinuria is usually the first laboratory finding that indicates renal involvement and, in most cases, this progresses to end-stage renal failure. The incidence rates of FMF-related amyloidosis in different ethnic groups vary widely. Several risk factors for more severe FMF or development of FMF-related amyloidosis have been identified: homozygosity for the M694V mutation and for the complex V726A-E148Q allele of MEFV, male gender, family history of FMF, and the α/α genotype for the serum amyloid A1 gene. However, results in the literature are conflicting with respect to possible relationships between the M694V mutation and the severity of FMF or development of FMF-related amyloidosis. Colchicine effectively reduces the frequency and duration of attacks in most FMF patients, and is the mainstay of treatment for this condition. This agent also helps prevent or arrest the development of amyloidosis in FMF patients.