Current Rheumatology Reviews - Volume 8, Issue 2, 2012

The fast technological progress of bio-medical research in the last decade led to the accumulation of vast amounts of data and opened new fields of research, such as epigenetics. Nevertheless, the pathogenesis of most complex diseases is still not understood. The current review discusses pathological changes in the adaptive immune system as well as in the synovium of rheumatoid arthritis (RA) patients. The main focus lies on epigenetic changes found in RA synovial cells, which might help to understand not only how environmental factors can influence disease development, but mainly why inflammation in RA joints is not resolved and why constant activation of the immune system and progressive joint destruction prevail.

Osteoarthritis (OA) is a multifactorial disease, typified by the loss of articular cartilage, with a strong genetic component. Current work, even with genome-wide association studies, has failed to identify the genes that describe the full genetic susceptibility to the disease. This is likely due to low penetrance polymorphisms in the population overall however, epigenetic mechanisms have been proposed to contribute to the heritability of the disease. Such epigenetic events that may play a role in OA progression and the gene expression changes observed in diseased cartilage have been identified by several studies. Epigenetic mechanisms include DNA methylation, histone modifications, and microRNAs which together, enable the cell to respond to environmental cues but when aberrant can be associated with a number of pathological conditions, including OA. In this review, we focus on microRNA, firstly on the identification and characterisation of those important for chondrogenesis then focussing on their disregulation in the disease. Although research on microRNAs in OA is in its infancy they merely represent the ‘tip of the non-coding RNA iceberg’. Future work, although initially focussed on microRNA, will undoubtedly expand to include the role of other such RNAs in skeletal development and disease.

MicroRNAs (miRNAs) are classes of non-coding RNA that function as negative regulators of protein-coding gene expression at the post-transcription level. It has been elucidated that the miRNAs play a critical role in a variety of human disease including arthritic diseases such as Rheumatoid arthritis (RA) and Osteoarthritis (OA). RA is a chronic autoimmune disease mainly characterized by the inflammation of synovial tissue that leads to destruction of the joint tissues, bone and cartilage. OA is characterized by the progressive destruction of articular cartilage. Recent studies elucidated that several miRNAs are abnormally expressed in RA and OA, and some of these intimately involved in the pathologies. The present review summarizes the current progress of miRNA synthesis and function, their expression and function in arthritis, especially focused on the well investigated miRNAs, miR-146a and miR-155.

Osteoclasts are primary cells for bone resorption, and their differentiation is tightly regulated by receptor activator of nuclear factor kappa B ligand (RANKL) and a transcription factor nuclear factor-activated T cells (NFAT) c1. Recent studies have uncovered that the epigenetic regulation such as DNA methylation, histone methylation and acetylation, and micro RNAs play a critical role in cell differentiation. In particular, the expression of key developmental genes tends to be tightly regulated by trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3). Several reports have been proposed regarding the epigenetic regulation of osteoclast differentiation including this specific histone modification change. RANKL-induced NFATc1 expression is associated with the demethylation of H3K27me3 in osteoclast precursors. Jumonji domain containing-3 (Jmjd3), a H3K27 demethylase, is induced in murine bone marrow-derived macrophages in response to RANKL stimulation, and supposedly plays a critical role in the demethylation of H3K27me3 in the Nfatc1 gene and osteoclast differentiation.

Ankylosing spondylitis (AS) is a disabling chronic inflammatory disease that mainly affects the axial skeleton with a special predilection for the sacro-iliac joints. Extensive evidence shows that Klebsiella pneumonia is the main microbial triggering factor in AS leading to the development of the full-blown disease after repeated attacks of infections by this microbe through mechanism of molecular mimicry or cross reactivity. Despite the use of advanced radiological tools, detection of early cases of AS is difficult and it takes nearly 5 to 10 years until the diagnosis of a classical AS is established, with as yet no available curative treatment. In the current review paper we present evidence for the role of Klebsiella microbes in the aetiopathogenesis of AS and discuss a possible new approach for early diagnosis of AS mainly through the identification of HLA-B27 antigens and Klebsiella antibodies, as well as treatment of AS with “low starch diet” with or without the use of current therapy.

Giant Cell Arteritis (GCA) is a chronic granulomatous vasculitis preferentially targeting large and mediumsized arteries but may be generalized; Vessel inflammation prominently involves the cranial branches of arteries originating in aortic arch. Headache is prevalent, appearing in two thirds of patients, classic in temporal region; may occur in occipital region or generalized accompanied in half a cases by “jaw claudication”. It is recognized today that this is in fact a systemic vasculitis with four possible phenotypes: large vessel vasculitis, cranial vasculitis, systemic inflammatory disease presentation and the polymyalgia rheumatica (PMR). Understanding the multiple aspects of Giant Cell Arteritis and the extensive involvement helps recognizing the dangerous complications: the vision loss, the aneurysms and dissecting aneurysms, the mesenteric insufficiency and the limb vascular occlusion and treat them. Scientific information now exists on the pathogenesis of GCA. Studies revealed the role of Th1 and Th17 cells and the network of cytokines and the implication in treatment. Studies in untreated and treated GCA patients have indicated that two cytokine networks contribute to the vasculitic immune pathology (IFN-γ axis and Il-17 axis). Also the majority of the studies have found a significant increased level of circulating IL-6 in patients with active disease Production of IL6 correlates with severity of systemic symptoms. The biopsy of temporal arteries is still the gold standard for diagnosis but the involvement of large vessels makes us look for the best studies to evaluate and re-evaluate after treatment that particular type of arteries. The review approaches studies that give information on vessel structure versus vessel inflammation (MRI/MRA, PET scan, and ultrasound). The first line of treatment is still the steroids, with a sense of urgency in complication to start sooner, use larger doses and decide on intravenous versus oral approach. Methotrexate and anti-tumor necrosis α inhibitors disappointed in studies and are not routinely recommended at this time. New treatments are connecting cytokine profile to its blocker trying to be more specific in managing a certain phenotype of GCA.

Diet-derived natural ligands of the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors have been widely reported to activate PPAR signaling, modifying gene and protein expressions in a variety of cells and tissues. Examples of such dietary factors include unsaturated fatty acids, spices, soy protein, and polyphenols. Recent data suggest that these nutrients may affect inflammation and immunity in arthritic diseases. This review describes these nutrients and their potential modulating effects on the pathophysiology of inflammatory and degenerative arthritis through PPAR signaling.

Osteoporosis, a widespread clinical disorder causing bones to become brittle, and liable to fracture, especially among postmenopausal women, is a highly disabling health condition. While hormone replacement therapy (HRT) has been effectively applied to offset this problem, long term HRT usage commonly yields highly detrimental side-effects. Since the prevalence of disabling osteoporosis continues to increase, and pharmacologic interventions are not risk free, examining alternative approaches to preserving bone mass among women as they age remains of considerable import. To this end, this work provides an updated synthesis of the recent literature detailing the rationale for, plus the known efficacy of aerobic exercises for preventing osteoporosis among postmenopausal women. It examines the effect of aerobic exercises on bone density, particular at the hip joint, a common fracture site resulting in high rates of morbidity and mortality. Using PUBMED, MEDLINE, WEB OF SCIENCE, and CINAHL databases, a diverse body of data revealed support for the application of moderate, prolonged aerobic exercise for improving bone density of postmenopausal women with few side-effects. Furthermore, along with their ability to impact bone density at the hip joint and other sites, due to their associated cognitive and muscle neuromuscular benefits, moderate intensity aerobic exercises appear promising for preventing falls that lead to fractures. Pending further well-designed and well-controlled longitudinal studies, it is concluded clinicians can safely recommend moderate intensity aerobic exercises alone or in combination with strengthening exercises to their premenopausal or perimenopausal clients in efforts to offset the anticipated excess bone losses and osteoporotic- related hip fractures and others commonly experienced by postmenopausal women.