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ID PMID Title PublicationDate abstract
24298040 Methods for the detection of peptidylarginine deiminase (PAD) activity and protein citrull 2014 Feb The post-translational conversion of peptidylarginine to peptidylcitrulline, a process also known as citrullination, is catalyzed by the enzyme family of peptidylarginine deiminases (PADs) and has been demonstrated to be involved in many physiological processes, including the regulation of gene expression. In addition, citrullination has been shown to be associated with several diseases, such as cancer, multiple sclerosis, rheumatoid arthritis, and Alzheimer's disease. To get more insight into the role of PAD enzymes and citrullination in both health and disease, experimental strategies to study PAD activity and to characterize citrullinated proteins in complex biological samples are crucial. Here, we describe the chemical, proteomic and antibody-based procedures that are currently available and discuss their applicability for the analysis of complex samples. The methods that have been developed can be used to provide more insight in the substrate specificity of PAD enzymes. Because the evidence that PADs play a pathophysiological role in the diseases mentioned above is increasing, they become attractive targets for therapeutic interventions. More knowledge of PAD specificity and the availability of reliable, high-throughput assays for PAD activity will facilitate the development of highly specific PAD inhibitors.
24281789 Effect of treating psoriasis on cardiovascular co-morbidities: focus on TNF inhibitors. 2014 Feb Psoriasis patients are at increased risk for cardiovascular disease. Literature on rheumatoid arthritis has shown the association of treatment with tumor necrosis factor (TNF) inhibitors and improvement of cardiovascular disease. Recent literature has also shown similar findings in psoriasis patients. We present a review of the literature on the effect of TNF inhibitors for psoriasis treatment on cardiovascular disease, cardiovascular biomarkers, and insulin resistance. We conclude that TNF inhibitors may be especially beneficial in preventing myocardial infarction, to a degree greater than methotrexate, especially in the Caucasian population. The effects of TNF inhibitors in altering insulin sensitivity or preventing new onset diabetes have been contradictory. Case reports of both hyperglycemia and hypoglycemia developing in patients under TNF inhibitor treatment teach us to warn patients about these side effects. More robust clinical studies are needed to evaluate the true effect of TNF inhibitors in diabetic psoriasis patients. More studies are also needed to assess the effect of TNF inhibitors on hypertension, dyslipidemia, and stroke.
24193188 [Established medications : new areas of application]. 2013 Nov During the last 10 years several new medications from hemato-oncology and transplantation medicine have been transferred to rheumatology. Additionally, medications which are approved for rheumatoid arthritis were increasingly also studied and used for other systemic inflammatory rheumatic diseases. This is especially the case for rituximab and mycophenolate and to a lesser extent also for leflunomide, tumor necrosis factor (TNF) antagonists, tocilizumab and abatacept. Recently, rituximab was approved for severe granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) after the publication of two prospective randomized trials in 2010. The situation concerning rituximab is much more problematic for systemic lupus erythematosus (SLE) where randomized placebo-controlled trials exist but unfortunately did not meet the primary endpoint requirements (too many highly effective additional forms of treatment in both arms and unsuitable endpoints), although data from registries suggest efficacy especially in cases resistant to treatment. In the case of mycophenolate (MPS) the problem with SLE is totally different. All prospective trials met the endpoints and in one trial MPS was even superior to azathioprine for treatment of lupus nephritis (LN) which led to the recommendation of MPS for induction and maintenance in LN by EULAR and EDTRA as well as more recently by the ACR. However, MPS still is not approved for SLE or LN. The present manuscript gives an overview of existing data for selected connective tissue diseases and vasculitides (for which at least larger retrospective case series or registry data exist) being treated with medications approved for other indications.
24158685 Administration of teriparatide treatment for a challenging case of nonunion of periprosthe 2013 INTRODUCTION: Management of a periprosthetic fracture after total knee arthroplasty is often challenging because it typically occurs in elderly patients, who often have osteoporotic bone with a high risk of delayed union and nonunion. Thus, administration of a medication that could effectively accelerate fracture healing to prevent a delayed union or nonunion should significantly improve treatment outcome and patient's quality of life. CASE PRESENTATION: We report the case of a 74-year-old rheumatoid arthritis woman with nonunion of a periprosthetic fracture after total knee arthroplasty, in whom bone union could not be achieved even after she underwent internal fixation and bone grafting twice; however, successful bone fusion was achieved after simple once-weekly administration of teriparatide for 6 months. DISCUSSION: Although we report only one patient, the present case may suggest the advantage of preventive administration of teriparatide in addition to surgical procedures for treating nonunion of a periprosthetic fracture after total knee arthroplasty.
24117769 Multinucleate cell angiohistiocytoma with hypertrophic nerves. 2013 Dec Multinucleate cell angiohistiocytoma (MCAH) represents a rare benign skin lesion characterized by multiple papules that are usually found on the distal extremities or face of middle-aged women. We report on a 60-year-old male with a history of monoclonal gammopathy and severe rheumatoid arthritis who had several asymptomatic red-to-livid papules grouped on the right side of his trunk. The lesions had been present for a few years and were gradually enlarging. Biopsies from three lesions showed a spectrum of changes consisting of a proliferation of small venules together with thickened collagen bundles and increased numbers of interstitial cells including bizarre, multinucleated giant cells. Immunohistochemically, the multinucleated cells were positive for vimentin and lysozyme while the interstitial cells expressed CD68, factor XIIIa and lysozyme. Interestingly, strikingly enlarged dermal nerves were seen in all the three biopsies and two of the biopsies showed an accompanying infiltrate of lymphocytes and plasma cells.
23631586 Periodontal systemic associations: review of the evidence. 2013 Apr AIM: To critically appraise recent research into associations between periodontal disease and systemic diseases and conditions specifically respiratory disease, chronic kidney disease, rheumatoid arthritis, cognitive impairment, obesity, metabolic syndrome and cancer. METHODS: A MEDLINE literature search of papers published between 2002 and April 2012 was conducted. Studies that included periodontitis as an exposure were identified. Cross-sectional epidemiological investigations on large samples, prospective studies and systematic reviews formed the basis of the narrative review. A threshold set for the identification of periodontitis was used to identify those studies that contributed to the conclusions of the review. RESULTS: Many of the investigations were cross-sectional secondary analyses of existing data sets in particular the NHANES studies. There were a small number of systematic reviews and prospective studies. There was substantial variability in the definitions of exposure to periodontitis. A small number of studies met the threshold set for periodontitis and supported associations; however, in some of the chronic diseases there were no such studies. There was strong evidence from randomized controlled trials that interventions, which improve oral hygiene have positive effects on the prevention of nosocomial pneumonias. CONCLUSIONS: There was substantial heterogeneity in the definitions used to identify periodontitis and very few studies met a stringent threshold for periodontitis. Published evidence supports modest associations between periodontitis and some, although not all, of the diseases and conditions reviewed. There is a need to reach a consensus on what constitutes periodontitis for future studies of putative associations with systemic diseases.
23571274 Regulation of circulating neutrophil numbers under homeostasis and in disease. 2013 Neutrophils are the most abundant circulating leukocyte and play a fundamental role in the innate immune response. Patients with neutropenia, leukocyte adhesion deficiency syndrome or chronic granulomatous disease are particularly prone to bacterial and fungal infection. However, the highly destructive capacity of these cells also increases the potential for neutrophil damage to healthy tissues, as seen in a number of inflammatory diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease. The homeostatic control of circulating neutrophil levels is thus critical, as an imbalance can result in overwhelming infection or inappropriate inflammatory states. Neutrophil homeostasis is maintained by a fine balance between granulopoiesis in the bone marrow, retention in and release from the bone marrow and clearance and destruction. This review discusses the molecular mechanisms regulating neutrophil mobilization from the bone marrow, with emphasis on the antagonistic roles of the CXCR4 (C-X-C motif receptor 4)/CXCL12 (C-X-C motif ligand 12) and CXCR2/ELR+ (Glu-Leu-Arg) CXC chemokine signaling axes in the bone marrow. A role for the CXCL12/CXCR4 chemokine axis in the trafficking of senescent neutrophils back to the bone marrow for clearance, along with the role of bone marrow macrophages and the molecules that mediate neutrophil clearance by bone marrow macrophages, is also discussed.
23455471 Phospholipases of mineralization competent cells and matrix vesicles: roles in physiologic 2013 Mar 1 The present review aims to systematically and critically analyze the current knowledge on phospholipases and their role in physiological and pathological mineralization undertaken by mineralization competent cells. Cellular lipid metabolism plays an important role in biological mineralization. The physiological mechanisms of mineralization are likely to take place in tissues other than in bones and teeth under specific pathological conditions. For instance, vascular calcification in arteries of patients with renal failure, diabetes mellitus or atherosclerosis recapitulates the mechanisms of bone formation. Osteoporosis-a bone resorbing disease-and rheumatoid arthritis originating from the inflammation in the synovium are also affected by cellular lipid metabolism. The focus is on the lipid metabolism due to the effects of dietary lipids on bone health. These and other phenomena indicate that phospholipases may participate in bone remodelling as evidenced by their expression in smooth muscle cells, in bone forming osteoblasts, chondrocytes and in bone resorbing osteoclasts. Among various enzymes involved, phospholipases A1 or A2, phospholipase C, phospholipase D, autotaxin and sphingomyelinase are engaged in membrane lipid remodelling during early stages of mineralization and cell maturation in mineralization-competent cells. Numerous experimental evidences suggested that phospholipases exert their action at various stages of mineralization by affecting intracellular signaling and cell differentiation. The lipid metabolites-such as arachidonic acid, lysophospholipids, and sphingosine-1-phosphate are involved in cell signaling and inflammation reactions. Phospholipases are also important members of the cellular machinery engaged in matrix vesicle (MV) biogenesis and exocytosis. They may favour mineral formation inside MVs, may catalyse MV membrane breakdown necessary for the release of mineral deposits into extracellular matrix (ECM), or participate in hydrolysis of ECM. The biological functions of phospholipases are discussed from the perspective of animal and cellular knockout models, as well as disease implications, development of potent inhibitors and therapeutic interventions.
23452331 On dihydroorotate dehydrogenases and their inhibitors and uses. 2013 Apr 25 Proper nucleosides availability is crucial for the proliferation of living entities (eukaryotic cells, parasites, bacteria, and virus). Accordingly, the uses of inhibitors of the de novo nucleosides biosynthetic pathways have been investigated in the past. In the following we have focused on dihydroorotate dehydrogenase (DHODH), the fourth enzyme in the de novo pyrimidine nucleosides biosynthetic pathway. We first described the different types of enzyme in terms of sequence, structure, and biochemistry, including the reported bioassays. In a second part, the series of inhibitors of this enzyme along with a description of their potential or actual uses were reviewed. These inhibitors are indeed used in medicine to treat autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (leflunomide and teriflunomide) and have been investigated in treatments of cancer, virus, and parasite infections (i.e., malaria) as well as in crop science.
23331685 Stem cell therapy in veterinary dermatology. 2013 Feb BACKGROUND: Adult stem cells come from many sources and have the capacity to differentiate into many cell types, including those of the skin. The most commonly studied stem cells are those termed mesenchymal stem cells (MSCs), which are easily isolated from bone marrow and adipose tissue. Mesenchymal stem cells are known to produce a wide array of cytokines that modulate the regeneration process. The ease of collection, propagation and use of these MSCs in therapy of traumatic, ischaemic and immune-mediated skin conditions is emerging. APPROACH AND EVIDENCE: In traumatic and ischaemic skin damage, MSCs are used in tissue-engineered skin and by direct injection into damaged tissue. For immune-mediated diseases, systemic administration of stem cells can modulate the immune system. The earliest clinical work has been with autologous stem cell sources, such as adipose tissue and bone marrow. In immune-mediated diseases, the MSCs are used to downregulate production of inflammatory cytokines and to block T-cell activation. Cells are generally given intravenously. Multiple sclerosis, rheumatoid arthritis and lupus have been successfully treated in human clinical trials. Mesenchymal stem cells can also stimulate resident local cells, such as keratinocytes and progenitor cells, to proliferate, migrate and repair skin injury and disease. LOOKING AHEAD: The discovery of the MSC in adipose tissue has spawned a global effort to utilize these cells in therapy of a wide range of diseases of the skin. Reconstructive surgery, scar blocking and resolution and skin regeneration have all been shown to be possible in human and animal studies.
23313291 Quantitative determination of human interleukin 22 (IL-22) in serum using Singulex-Erenna 2013 Apr 30 Interleukin-22 (IL-22) is a key mediator of inflammatory processes associated with diseases such as psoriasis, inflammatory bowel disease and rheumatoid arthritis. The measurement of this cytokine in human plasma may provide insight into safety, pharmacodynamics and efficacy of drugs targeting inflammatory pathways. However, commonly used immunoassays are not sufficiently sensitive to measure baseline concentrations of IL-22. Here we describe the analytical validation of an ultrasensitive assay for the measurement of IL-22 in human serum using the Erenna® system by Singulex (Alameda, CA). The lower limit of quantification (LLOQ) of the Erenna assay estimated at 0.2pg/mL was sensitive enough to measure IL-22 in all human serum samples tested. The assay ranged from 0.2 to 100.0pg/mL and showed good dilution linearity. The inter-assay and intra-assay imprecision were <9% and <7% CV respectively. The accuracy determined by spiked recovery in serum samples was >86%. In addition, the results using Erenna assay correlated well with those using the IL-22 Quantikine immunoassay (R&D Systems, Minneapolis, MN) with a coefficient R(2) of 0.9285. However the Erenna assay showed an improved sensitivity by approximately 2 logs. These results show that this novel assay offers a significant improvement over previous methods for high-sensitive quantitative measurement of IL-22 in human serum samples.
23016823 Effect of non-steroidal anti-inflammatory drugs on bone turnover: an evidence-based review 2013 Mar Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for acute and chronic pain control and treatment of inflammation, osteoarthritis and rheumatoid arthritis. NSAIDs have been shown to inhibit bone healing in animal studies due to the inhibition of prostaglandin synthesis. However, little evidence exists regarding the effect of NSAID exposure on human bone metabolism. This systematic review summarizes the current literature of randomized controlled trials (RCTs) investigating NSAIDs with bone remodeling-related outcomes in humans. After performing computerized searches in the most widely indexed databases, study selection, data abstraction and risk of bias assessment were conducted in duplicate. The results were controversial regarding the association of NSAID with bone formation or resorption. Increased bone mineral density following NSAID exposure was reported by some studies. Based on the levels of biochemical markers, no effect was seen on bone formation, while some evidence was found for a decreased rate of bone resorption in NSAID patients. Trials investigating the effects of NSAID treatment on bone metabolism outcomes of human patients are limited. Further research is required to confirm or refute the findings of this systematic review.
22231516 Type I interferons: beneficial in Th1 and detrimental in Th17 autoimmunity. 2013 Apr In relapsing remitting multiple sclerosis (RRMS), type I interferon (IFN) is considered immuno-modulatory, and recombinant forms of IFN-β are the most prescribed treatment for this disease. However, within the RRMS population, 30-50% of MS patients are nonresponsive to this treatment, and it consistently worsens neuromyelitis optica (NMO), a disease once considered to be a form of RRMS. In contrast to RRMS, type I IFNs have been shown to have properties that drive the inflammatory pathologies in many other autoimmune diseases. These diseases include Sjögren's syndrome, system lupus erythematosus (SLE), neuromyelitis optica (NMO), rheumatoid arthritis (RA) and psoriasis. Historically, autoimmune diseases were thought to be driven by a TH1 response to auto-antigens. However, since the discovery of the TH17 in experimental autoimmune encephalomyelitis (EAE), it is now generally thought that TH17 plays an important role in MS and all other autoimmune diseases. In this article, we will discuss recent clinical and basic research advances in the field of autoimmunity and argue that IFN-β and other type I IFNs are immuno-modulatory in diseases driven predominantly by TH1 but in contrast are inflammatory in diseases that have a predominant Th17 response.
24497495 Brief report: prevalence of antineutrophil cytoplasmic antibodies in infective endocarditi 2014 Jun OBJECTIVE: Infective endocarditis (IE) mimics primary systemic vasculitis, and there are sporadic reports of positivity for antineutrophil cytoplasmic antibodies (ANCAs) among patients with IE. Because the frequency of ANCAs in IE is unknown, this study was undertaken to assess the seroprevalence of ANCAs in a large number of patients with IE. METHODS: The study was conducted in the framework of a single-center prospective cohort study of incident IE cases. Demographic, clinical, laboratory, and microbiologic data were collected, and magnetic resonance imaging of the brain was performed at diagnosis. For those patients whose serum had been stored at diagnosis, ANCAs were assessed by indirect immunofluorescence assay in ethanol-, formalin-, and methanol-fixed neutrophils. In addition, ANCA specificity for proteinase 3 (PR3) and myeloperoxidase (MPO) was assessed by enzyme-linked immunosorbent assay. Rheumatoid factor (RF), antinuclear antibodies (ANAs), anticardiolipin antibodies (aCL), and serum Ig levels were also measured. Comparisons between groups were made using Wilcoxon's rank sum and chi-square or Fisher's exact tests. RESULTS: Among 109 patients with IE, 18% had cytoplasmic ANCAs (cANCA) and/or perinuclear ANCAs (pANCA) and 8% had PR3-ANCAs or MPO-ANCAs, some with very high titers. Positivity for both cANCA or pANCA and PR3-ANCAs or MPO-ANCAs was found in 6% of patients, and RF, ANAs, and aCL were detected in 35%, 16%, and 23% of samples, respectively. No consistent clinical pattern of IE was observed in the anti-PR3/anti-MPO-positive IE patients, whereas positivity for cANCA/pANCA was associated with younger age (P = 0.022), more frequent occurrence of echocardiographic vegetations (P = 0.043), and above-normal serum IgG levels (P = 0.017). CONCLUSION: ANCAs, including PR3- and MPO-ANCAs, occur in a substantial proportion of patients with IE. The link between cANCA/pANCA and specific features of IE requires further study.
24966280 Inflammatory joint disease in cats: diagnostic approach and treatment. 2014 Jul PRACTICAL RELEVANCE: Osteoarthritis, a degenerative non-inflammatory joint disease, is common in cats, usually causing gradual changes in behavior and lifestyle rather than severe lameness. Inflammatory arthritis occurs much less frequently and is nearly always associated with debilitating lameness. It may have an infectious or immune-mediated cause - but, unlike the canine disease, is much more likely to be infectious in origin. CLINICAL CHALLENGES: Cats with inflammatory joint disease are presented for evaluation of lethargy, anorexia, reluctance to walk or fever. Synovial fluid collection and analysis is required to confirm joint inflammation, but this is a procedure many veterinarians are not comfortable performing in cats. Once inflammatory arthritis is confirmed, extensive testing is required to diagnose infectious causes and determine appropriate treatment. Immune-mediated polyarthritis can be treated with immunosuppressive drugs only after all infectious possibilities are eliminated. Radiographs are used to characterize the arthritis as erosive or nonerosive, but radiographic changes in cats are often subtle compared with those described in canine rheumatoid-like arthritis. AUDIENCE: This review, aimed at all veterinarians who treat cats, describes the general clinical approach to feline joint disease, the collection and analysis of synovial fluid, and the diagnosis and management of inflammatory joint diseases affecting cats. The diagnostic approach to an unusual case of erosive polyarthritis is discussed in the Case Notes. EVIDENCE BASE: To date, the veterinary literature on inflammatory joint disease in cats has been limited to older reviews of immune-mediated disorders and multiple single case reports or small case series describing infectious disorders. This article offers a current comprehensive review of these disorders.
24341611 Nanomedicines for inflammatory arthritis: head-to-head comparison of glucocorticoid-contai 2014 Jan 28 As an emerging research direction, nanomedicine has been increasingly utilized to treat inflammatory diseases. In this head-to-head comparison study, four established nanomedicine formulations of dexamethasone, including liposomes (L-Dex), core-cross-linked micelles (M-Dex), slow releasing polymeric prodrugs (P-Dex-slow), and fast releasing polymeric prodrugs (P-Dex-fast), were evaluated in an adjuvant-induced arthritis rat model with an equivalent dose treatment design. It was found that after a single i.v. injection, the formulations with the slower drug release kinetics (i.e., M-Dex and P-Dex-slow) maintained longer duration of therapeutic activity than those with relatively faster drug release kinetics, resulting in better joint protection. This finding will be instructional in the future development and optimization of nanomedicines for the clinical management of rheumatoid arthritis. The outcome of this study also illustrates the value of such head-to-head comparison studies in translational nanomedicine research.
24453256 PTPN22 controls the germinal center by influencing the numbers and activity of T follicula 2014 Feb 15 A single nucleotide polymorphism in PTPN22 (R620W), which encodes the Lyp tyrosine phosphatase, has been linked to a number of autoimmune diseases including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Studies in PTPN22 knockout (KO) mice and in mice expressing the mouse homolog of the pro-autoimmune allele, PEP(R619W), have reported increased germinal center activity and enhanced Ab production. In this article, we present findings that explain the basis for increased germinal center activity in PTPN22 mutant mice. As compared with their wild type equivalents, T follicular helper cells from PTPN22 KO mice proliferate and accumulate to a greater extent, and exhibit enhanced production of IL-21. The follicular regulatory T cells in PTPN22 KO mice do not expand to effectively regulate these T follicular helper cells, resulting in an increase in B cell numbers and Ab production. This is evident in the KBxN mouse model of arthritis in which PTPN22 deficiency results in increased severity of disease. Our findings demonstrate the importance of cell type-specific PTPN22 activity on regulation of Ab production.
25343509 The coexistence of antiphospholipid syndrome and systemic lupus erythematosus in Colombian 2014 OBJECTIVES: To examine the prevalence and associated factors related to the coexistence of antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) in a cohort of Colombian patients with SLE, and to discuss the coexistence of APS with other autoimmune diseases (ADs). METHOD: A total of 376 patients with SLE were assessed for the presence of the following: 1) confirmed APS; 2) positivity for antiphospholipid (aPL) antibodies without a prior thromboembolic nor obstetric event; and 3) SLE patients without APS nor positivity for aPL antibodies. Comparisons between groups 1 and 3 were evaluated by bivariate and multivariate analysis. RESULTS: Although the prevalence of aPL antibodies was 54%, APS was present in just 9.3% of SLE patients. In our series, besides cardiovascular disease (AOR 3.38, 95% CI 1.11-10.96, p = 0.035), pulmonary involvement (AOR 5.06, 95% CI 1.56-16.74, p = 0.007) and positivity for rheumatoid factor (AOR 4.68, 95%IC 1.63-14.98, p = 0.006) were factors significantly associated with APS-SLE. APS also may coexist with rheumatoid arthritis, Sjögren's syndrome, autoimmune thyroid diseases, systemic sclerosis, systemic vasculitis, dermatopolymyositis, primary biliary cirrhosis and autoimmune hepatitis. CONCLUSIONS: APS is a systemic AD that may coexist with other ADs, the most common being SLE. Awareness of this polyautoimmunity should be addressed promptly to establish strategies for controlling modifiable risk factors in those patients.
24590181 The global burden of other musculoskeletal disorders: estimates from the Global Burden of 2014 Aug OBJECTIVE: To estimate disability from the remainder of musculoskeletal (MSK) disorders (categorised as other MSK) not covered by the estimates made specifically for osteoarthritis (OA), rheumatoid arthritis (RA), gout, low back pain and neck pain, as part of the Global Burden of Disease (GBD) 2010 study. METHODS: Systematic reviews were conducted to gather the age-sex-specific epidemiological data for other MSK. The focus was on finding health surveys and published studies that measured the overall amount of MSK disorders and complaints, and classified the remainder of MSK disorders that was not RA, OA, gout, low back or neck pain. Six levels of severity were defined to derive disability weights (DWs) and severity distribution. The data, DWs and severity distribution were used to calculate years of life lived with disability (YLDs). Mortality was estimated for MSK-related deaths classified under other MSK. YLDs were added to years of life lost (YLLs) from the mortality estimates to derive overall burden in disability-adjusted life years (DALYs). RESULTS: Global prevalence of other MSK was 8.4% (95% uncertainty interval (UI) 8.1% to 8.6%). DALYs increased from 20.6 million (95% UI 17.0 to 23.3 million) in 1990 to 30.9 million (95% UI 25.8 to 34.6 million) in 2010. The burden of other MSK increased with age. Globally, other MSK disability burden (YLD) ranked sixth. CONCLUSIONS: Ageing of the global population will further increase the burden of other MSK. Specific MSK conditions within this large category should be considered separately to enable more explicit estimates of their burden in future iterations of GBD.
23830916 Expression of metastasin S100A4 is essential for bone resorption and regulates osteoclast 2013 Dec OBJECTIVE: S100A4 is a Ca-binding protein that regulates cell growth, survival, and motility. The abundant expression of S100A4 in rheumatiod arthritis contributes to the invasive growth of joint tissue and to bone damage. In the present study, we analysed the role of S100A4 in bone homeostasis. METHODS: Peripheral quantitative computed tomography and histomorphometric analysis were performed in mice lacking the entire S100A4 protein (S100A4KO) and in wild-type (WT) counterparts treated with shRNA-lentiviral constructs targeting S100A4 (S100A4-shRNA). Control groups consisted of sex-matched WT counterparts and WT mice treated with a non-targeting RNA construct. RESULTS: S100A4 deficiency was associated with higher trabecular and cortical bone mass, increased number and thickness of trabeculi combined with larger periosteal circumference and higher predicted bone strength. S100A4 inhibition by shRNA led to an increase in cortical bone in WT mice. S100A4-deficieny was associated with a reduced number of functional osteoclasts. S100A4KO and S100A4-shRNA-treated bone marrow progenitors gave rise to a large number of small TRAP+ cells with few nuclei and few pseudopodial processes. Poor osteoclastogenesis and the low resorptive capacity in S100A4Ko mice may be linked to low levels of surface integrins, impaired adhesion capacity, and poor multinucleation in S100A4-deficient osteoclasts, as well as a low content of proteolytic enzymes cathepsin K and MMP3 and MMP9 to break down the organic matrix. CONCLUSION: S100A4 emerges as a negative regulator of bone metabolism potentially responsible for the excessive bone turnover in conditions marked by high levels of S100A4 protein, such as inflammation and rheumatoid arthritis.