osteoprotegerin and Arthritis--Psoriatic

Psoriatic arthritis (PsA) is an inflammatory rheumatic disorder that occurs in patients with psoriasis and predominantly affects musculoskeletal structures, skin, and nails. The etiology of PsA is not well understood but evidence supports an interplay of genetic, immunologic, and environmental factors which promote pathological bone remodeling and joint damage in PsA. Localized and systemic bone loss due to increased activity of osteoclasts is well established in PsA based on animal models and translational studies. In contrast, the mechanisms responsible for pathological bone remodeling in PsA remain enigmatic although new candidate molecules and pathways have been identified. Recent reports have revealed novel findings related to bone erosion and pathologic bone formation in PsA. Many associated risk factors and contributing molecular mechanisms have also been identified. In this review, we discuss new developments in the field, point out unresolved questions regarding the pathogenetic origins of the wide array of bone phenotypes in PsA, and discuss new directions for investigation.

Topics: Animals; Arthritis, Psoriatic; Bone and Bones; Bone Remodeling; Bone Resorption; Humans; Osteoclasts; Osteoprotegerin

In rheumatic diseases, biomarkers may serve as surrogate endpoints for diagnosis, prognosis, disease activity, therapeutic response and disease outcome. In recent years a great effort has been made to identify useful tools to establish early diagnosis, prognosis and therapeutic response especially in rheumatoid arthritis (RA). In psoriatic arthritis (PsA) serological biomarkers have been frequently borrowed from RA, but this approach have sometimes lead to inappropriate choices of biomarkers and incorrect conclusions. Furthermore, the heterogeneous spectrum of articular manifestation of PsA and the variable course of the disease can make diagnosis and prognosis difficult. Recently, the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) identified two key areas for biomarkers development in psoriasis and PsA: the diagnosis of the articular disease in patients with psoriasis and the evaluation of joint damage in PsA. In this review we revised the currently available and the new potential markers for PsA, such as serum, genetic, cellular and histological biomarkers, clinical and imaging data, with particular attention on the prognostic aspect in order to identify progressive disease suitable for a more aggressive treatment.

Topics: Arthritis, Psoriatic; Autoantibodies; Autoantigens; Biomarkers; Blood Sedimentation; Bone Remodeling; C-Reactive Protein; Cartilage Oligomeric Matrix Protein; Cytokines; Diagnostic Imaging; Disease Progression; Extracellular Matrix Proteins; Genetic Predisposition to Disease; Humans; Joints; Osteoprotegerin; Peptides, Cyclic; Prognosis; Treatment Outcome

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy that can be associated with focal bone erosions. Psoriasis usually precedes the psoriatic arthritis onset by an average of 10 years, but this relation is not yet fully elucidated. Pro-inflammatory cytokines, such as IL-33, OPN, IL-17, and TNF-α are involved in both psoriasis and PsA pathogenesis as well as in bone homeostasis. In this study, we have demonstrated that IL-33, OPN, IL-17, and TNF-α induced the release of a wide range of pro-osteoclastogenic factors from the skin, such as RANKL, that promote monocyte differentiation in osteoclasts. The addition of osteoprotegerin, a RANKL inhibitor, to monocyte cultures treated with supernatant from stimulated skin did not completely deplete osteoclast formation, suggesting that skin produced several additional pro-osteoclastogenic mediators, which could act in a RANKL-independent manner. Moreover, we have found that RANKL serum levels as well as osteoclast number and activity in psoriatic patients with and without arthritis, was influenced by severity of cutaneous disease. Our data demonstrate that psoriatic cutaneous inflammation contributes to bone damage.

Topics: Adult; Arthritis, Psoriatic; Bone and Bones; Bone Resorption; Cytokines; Female; Humans; Inflammation; Interleukin-17; Interleukin-33; Male; Monocytes; Osteoclasts; Osteogenesis; Osteopontin; Osteoprotegerin; Psoriasis; RANK Ligand; Tumor Necrosis Factor-alpha; Young Adult

To evaluate the effect of anti-TNF treatments on bone mineral density (BMD), bone remodelling markers (BRM) and receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) in patients with chronic inflammatory joint diseases.. A longitudinal prospective study was performed under clinical practice conditions on 31 patients diagnosed of rheumatoid arthritis, psoriatic arthropathy and ankylosing spondylitis who had received treatment with anti-TNF alpha drugs for one year. BMD, OPG and RANKL soluble form (sRANKL) were studied at the onset and end of the study. During the study (0, 3, 6, 9 and 12 month), disease activity (SDAI, BASDAI and CRP), functional capacity (HAQ, BASFI), BRM and vitamin D were studied.. BMD was not modified after one year of treatment. The patients who took corticosteroids had a mean bone mass loss of 3% in the lumbar spine (±1.6, P=.02). In regards to the BRM, did not experience significant changes over the course of the study. Disease activity, both SDAI (P=.002) and BASDAI (P=.002), decreased. OPG was maintained without changes during the year of treatment while both the sRANKL (0.28±0.22, P=.013) and sRANKL/OPG ratio significantly decreased (0.04±0.03, P=.031).. The patients being treated with anti-TNF did not present with a significant loss of DMO during the study (one year), at the same time experiencing an improvement in disease activity. This protection has been clearer in the responding patients.

Topics: Adalimumab; Adult; Aged; Anti-Inflammatory Agents; Arthritis, Psoriatic; Arthritis, Rheumatoid; Biomarkers; Bone Density; Bone Remodeling; Chronic Disease; Etanercept; Female; Humans; Infliximab; Longitudinal Studies; Male; Middle Aged; Osteoprotegerin; Prospective Studies; RANK Ligand; Spondylitis, Ankylosing; Treatment Outcome; Tumor Necrosis Factor-alpha

We studied the impact of hypertension along with traditional and new cardiovascular risk factors on the structural and functional properties of arteries in psoriatic arthritis (PsA) patients. We examined 42 PsA subjects (aged 51±9 years) stratified according to hypertensive status (19 normotensive, PsA-NT and 23 hypertensives, PsA-HT). Thirty-eight normotensive subjects (C-NT) and 23 hypertensives (C-HT) comparable by age and sex served as controls. Mean carotid intima-media thickness (mean-IMT) and mean of the maximum IMT (M-Max) were evaluated by ultrasound in carotid artery segment bilaterally. Post-occlusion flow-mediated dilation (FMD) of the brachial artery was evaluated by ultrasonography. These parameters were correlated with risk factors, markers of inflammation and disease activity. Values of mean-IMT were higher in both groups of PsA patients compared with C-NT (0.68 mm in PsA-NT and 0.75 mm in PsA-HT versus 0.61 mm in C-NT). PsA-HT displayed higher M-Max (0.95 mm) versus both C-HT (0.71 mm) and PsA-NT (0.79 mm). FMD was impaired in PsA subjects compared with C-NT (5.7% in PsA-NT and 6.0% PsA-HT versus 9.3% in C-NT), whereas there was no difference among PsA-HT, PsA-NT, and C-HT groups. Values of carotid IMT were directly related to tumor necrosis factor (TNF)-α, osteoprotegerin (OPG), blood pressure and lipid profile levels. FMD showed an inverse relationship with TNF-α and blood pressure, but no correlation with lipids. In conclusion, PsA per se implies a pro-atherogenic remodeling, which is enhanced by the hypertensive status. TNF-α and OPG may have an independent role in the development of such vascular damage.

Topics: Adult; Arthritis, Psoriatic; Biomarkers; Brachial Artery; Carotid Arteries; Carotid Artery Diseases; Carotid Intima-Media Thickness; Case-Control Studies; Female; Humans; Hypertension; Inflammation Mediators; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Risk Factors; Tumor Necrosis Factor-alpha; Vasodilation

To identify soluble biomarkers associated with response to therapy with tumor necrosis factor inhibitors (TNFi) in patients with psoriatic arthritis (PsA).. The study was conducted at a PsA clinic where patients are assessed every 6 months, and serum samples are collected and stored once a year at the time of clinical assessment. Forty patients with active PsA who gave serum samples prior to treatment with TNFi and after at least 3 months of therapy were identified. Patients were classified as TNFi responders if tender joint count was < 3, swollen joint count was 0, and Psoriasis Area and Severity Index score was < 4 at the time the second sample was collected. The following biomarkers were tested by ELISA: TNF superfamily 14, matrix metalloprotease-3 (MMP-3), receptor activator of nuclear factor kappa-B ligand, osteoprotegerin, cartilage oligomeric matrix protein (COMP), CPII, C2C and C1-2C, CS-846, and highly sensitive C-reactive protein. Paired t tests and logistic regression was used for statistical analyses.. After a mean treatment duration of 11 months with TNFi (etanercept 28 patients, adalimumab 6, golimumab 4, infliximab 2), 29 patients were classified as TNFi responders. Baseline level of MMP-3 was independently associated with responder status (OR 1.067 for each 1-unit increase, p = 0.045). A reduction in MMP-3 levels with therapy increased the odds of achieving response (OR 1.213 for each 1-unit change, p = 0.030), whereas a reduction in COMP decreased the odds (OR 0.587, for each 100-unit increase, p = 0.039). None of the other biomarkers was associated with response.. Baseline as well as reduction in serum MMP-3 and increase in serum COMP are independently associated with response to TNFi therapy in patients with PsA.

Topics: Adalimumab; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Psoriatic; Biomarkers; Cartilage Oligomeric Matrix Protein; Etanercept; Female; Humans; Immunoglobulin G; Infliximab; Male; Matrix Metalloproteinase 3; Middle Aged; Osteoprotegerin; Receptors, Tumor Necrosis Factor; Severity of Illness Index; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Adrenal Cortex Hormones; Adult; Aged; Arthritis, Psoriatic; Bone Density; Case-Control Studies; Cross-Sectional Studies; Densitometry; Female; Fractures, Bone; Humans; Immunosuppressive Agents; Male; Middle Aged; Osteoporosis; Osteoprotegerin; Postmenopause; Premenopause; Prevalence; RANK Ligand; Tumor Necrosis Factor-alpha

Biomarkers may be used to screen patients with psoriasis for psoriatic arthritis (PsA) and to assess disease activity and severity. Candidate biomarkers should fulfil the key features of the OMERACT (Outcome Measures in Rheumatology) filter, that is, truth, discrimination, and feasibility. A number of biomarkers are currently being investigated in psoriatic disease for important clinical outcomes. Serum high sensitivity C-reactive protein, cartilage oligomeric matrix protein, interleukin 6 (IL-6), osteoprotegerin, matrix metalloprotease-3 (MMP-3), and the ratio of C-propeptide of type II collagen (CPII) to collagen fragment neoepitopes Col2-3/4 (long mono) (C2C) show promise as serum biomarkers that distinguish subjects with PsA from those with psoriasis alone. Serum MMP-3 and melanoma inhibitory activity, synovial fluid IL-1, IL-1 receptor-α, IL-6, IL-8, and chemokine CCL3 and synovial tissue CD3-positive T cells may prove useful as biomarkers of PsA activity. Circulating osteoclast precursors, Dickkopf-1, macrophage colony stimulating factor, receptor activator of nuclear factor-κB ligand, and bone alkaline phosphatase are strong candidates as biomarkers of radiographic change. Prospective studies to identify biomarkers for psoriatic disease are high on the research agenda of the Group for Research and Assessment of Psoriasis and PsA.

Topics: Arthritis, Psoriatic; Biomarkers; C-Reactive Protein; Cartilage Oligomeric Matrix Protein; CD3 Complex; Chemokine CCL3; Collagen Type II; Extracellular Matrix Proteins; Glycoproteins; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Matrilin Proteins; Matrix Metalloproteinase 3; Osteoprotegerin; Receptors, Interleukin-1 Type I; Severity of Illness Index; T-Lymphocytes

Patients with psoriatic arthritis (PsA) have a higher inflammatory burden and poorer quality of life compared to patients with psoriasis without PsA. Early identification of PsA may prevent joint damage progression and improve quality of life. Soluble biomarkers have the potential to be useful for screening patients with psoriasis for underlying PsA so that appropriate referral to a rheumatologist is made. Pilot studies have shown that C-reactive protein, interleukin 6, cartilage oligomeric matrix protein (COMP), Dickkopf-1, and macrophage-colony stimulating factor may differentiate PsA from psoriasis without PsA. Compared with controls, increased serum levels of receptor activator of nuclear factor-κB ligand, tumor necrosis factor superfamily member 14, matrix metalloproteinase-3 (MMP-3), and COMP are independently associated with psoriatic disease. Increased levels of high-sensitivity CRP (hsCRP), osteoprotegerin (OPG), MMP-3, and the ratio of C-propeptide of type II collagen (CPII) to collagen fragment neoepitopes Col2-3/4 C(long mono) (C2C) are independently associated with PsA. A combination of hsCRP, OPG, MMP-3, and the ratio CPII of C2C was able to distinguish patients with PsA from those with psoriasis alone in a receiver-operating characteristic curve analysis, with area under the curve 0.904. Therefore, a combination of the above biomarkers may at least have a role in screening patients with psoriasis for PsA. These findings need to be validated in prospective studies.

Topics: Arthritis, Psoriatic; Biomarkers; C-Reactive Protein; Diagnosis, Differential; Humans; Matrix Metalloproteinase 3; Osteoprotegerin; Peptide Fragments; Predictive Value of Tests; Procollagen; Prognosis; Psoriasis; ROC Curve

Significant bone remodeling with disordered osteoclastogenesis has been implicated in the pathogenesis of psoriatic arthritis (PsA). And there is a high prevalence of the metabolic syndrome (MS) in PsA patients. Adipokines, especially leptin and adiponectin, have recently been reported to be involved in the development and regulation of some autoimmune diseases. In this study, we examined the alternation of circulating osteoclastogenesis related cytokines [tumor necrosis factor-α (TNF-α), osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL)] and adipokines (leptin, adiponectin, resistin, chemerin, omentin) in PsA patients, and analysed the correlations between these factors and osteoclast precursors numbers, radiographic damage scores, and disease activity index. 41 PsA patients, 20 psoriasis patients, and 24 healthy controls were recruited. Blood samples were obtained for detecting the levels of TNF-α, OPG, RANKL and the adipokines. The numbers of osteoclast precursors (OCs) in peripheral blood were assessed. Radiographs of affected joints in PsA patients were scored for erosion, joint-space narrowing, osteolysis, and new bone formation. Compared with healthy controls, patients with PsA had higher TNF-α, RANKL, OCs, leptin and omentin but lower adiponectin and chemerin. Increased serum levels of TNF-α, RANKL, leptin, and omentin were positively correlated with OCs numbers. In contrast, serum adiponectin levels were decreased in PsA patients and negatively correlated with OCs numbers. TNF-α, RANKL and leptin were positively correlated with Psoriatic Arthritis Joint Activity Index (PsAJAI). Only TNF-α was positively correlated with radiographic damage scores. Our data demonstrated that systemic expression of soluble mediators of osteoclastogenesis and adipokines were disordered in PsA. Certain adipokines were elevated in the circulation of patients with PsA and might contribute to pathogenesis of arthritis. Prospective studies will be of interest to determine the pluripotent effects of adipokines on osteoclastogenesis in chronic inflammatory rheumatic diseases. Future studies may lead to novel therapeutic strategies.

Topics: Adipokines; Adiponectin; Adult; Aged; Analysis of Variance; Arthritis, Psoriatic; Bone Remodeling; Bone Resorption; Chemokines; Cytokines; Female; GPI-Linked Proteins; Humans; Intercellular Signaling Peptides and Proteins; Lectins; Leptin; Male; Middle Aged; Osteoclasts; Osteoprotegerin; RANK Ligand; Resistin; Tumor Necrosis Factor-alpha; Young Adult

TSG-6 (the product of tumor necrosis factor [TNF]-stimulated gene 6) has a potent inhibitory effect on RANKL-mediated bone erosion. The aim of this study was to compare the activity of TSG-6 with that of osteoprotegerin (OPG) and to investigate its role as an autocrine modulator of cytokine-mediated osteoclast formation/activation. We also determined TSG-6 expression in inflammatory joint disease.. The effects of TSG-6, OPG, and the inflammation mediators TNFα, interleukin-1 (IL-1), and IL-6 on the formation of osteoclasts from peripheral blood mononuclear cells and synovial fluid (SF) macrophages were determined by tartrate-resistant acid phosphatase staining. Lacunar resorption and filamentous actin ring formation were measured as indicators of osteoclast activity. The amount of TSG-6 in culture media or SF was quantified by enzyme-linked immunosorbent assay, and expression of TSG-6 in synovial tissue was assessed by immunohistochemistry.. TSG-6 acted in synergy with OPG to inhibit RANKL-mediated bone resorption and was produced by osteoclast precursors and mature osteoclasts in response to TNFα, IL-1, and IL-6. Expression of TSG-6 correlated with inhibition of lacunar resorption; this effect was ameliorated by an anti-TSG-6 antibody. The level of TSG-6 protein was determined in SF from patients with various arthritides; it was highest in patients with inflammatory conditions such as rheumatoid arthritis, in which it correlated with the amount of TSG-6 immunostaining in the synovium. TSG-6 inhibited the activation but not the formation of osteoclasts from SF macrophages.. In the presence of inflammatory cytokines, osteoclasts produced TSG-6 at concentrations that are sufficient to inhibit lacunar resorption. This may represent an autocrine mechanism to limit the degree of bone erosion during joint inflammation.

Topics: Aged; Arthritis, Psoriatic; Arthritis, Rheumatoid; Autocrine Communication; Bone Resorption; Cell Adhesion Molecules; Cell Differentiation; Cells, Cultured; Female; Humans; Interleukin-1; Interleukin-6; Macrophages; Male; Osteoarthritis, Knee; Osteoclasts; Osteoprotegerin; Tumor Necrosis Factor-alpha

The most frequent extracutaneous association with psoriasis is arthritis. Because proinflammatory cytokines are increased in psoriasis, patients with this disease may be more prone to osteoporosis than the healthy individuals.. We evaluated 50 patients with psoriasis, with or without psoriatic arthritis (PsA), for the presence and degree of osteoporosis by performing dual energy x-ray absorptiometry (DEXA) and obtaining serum osteoprotegrin (OPG) levels. In addition, we correlated these results with the extent of skin and joint disease. Psoriasis area and severity index (PASI) was determined in all 50 patients with psoriasis, and total joint score (TJS) was recorded in the 16 patients who also had PsA. Results of DEXA and serum OPG were also obtained for 20 healthy individuals who served as controls.. Osteoprotegrin level was significantly increased in psoriasis patients (with or without PsA) vs. controls. However, DEXA revealed that PsA patients had a higher degree of osteoporosis in the femur neck and wrist. In PsA patients, TJS correlated positively with both disease duration and PASI but correlated negatively with Z score of the femur.. Psoriasis patients with or without arthritis may suffer from osteoporosis as evidenced by significantly increased serum OPG. Prolonged and extensive cutaneous disease is an important risk factor for the development and severity of PsA. Patients with a greater number of affected joints are at higher risk of osteoporosis.

Topics: Absorptiometry, Photon; Adult; Arthritis, Psoriatic; Female; Femur; Humans; Male; Middle Aged; Neck; Osteoporosis; Osteoprotegerin; Psoriasis; Severity of Illness Index; Wrist; Young Adult

Psoriasis (Ps) and psoriatic arthritis (PsA) are diseases of unknown origin. However, the receptor activator nuclear factor κ B ligand (RANKL) might play a key role in the pathomechanisms of the disease. Our aim was to study seven single nucleotide polymorphisms (SNP) in the genes encoding for receptor activator nuclear factor κ B (RANK, two SNP), osteoprotegerin (OPG, two SNP) and RANKL (three SNP in patients with Ps and PsA). A case-control study with 156 Ps patients (45 with PsA) and 516 healthy blood donors was conducted to evaluate an association of the SNP with Ps and PsA by genotyping of DNA by polymerase chain reaction. None of the seven SNP showed any differences in the allelic or genotype frequencies between Ps patients and controls. Our study showed no significant association between the SNP in the genes encoding for RANK, OPG and RANKL with susceptibility of disease in Ps and PsA patients.

Topics: Adolescent; Adult; Aged; Alleles; Arthritis, Psoriatic; Case-Control Studies; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Osteoprotegerin; Polymorphism, Single Nucleotide; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Young Adult

Diverse bone pathologies are observed in patients with psoriatic arthritis (PsA). Uncoupling of bone remodeling with disordered osteoclastogenesis has been implicated in the pathogenesis of PsA. The aim of this study was to examine the role of soluble mediators of bone remodeling within the circulation of patients with PsA.. Patients with PsA (n = 38), with psoriasis (n = 10), and healthy controls (n = 12) were studied. Serum was obtained for testing of Dikkopf-1 (Dkk-1), macrophage-colony stimulating factor (M-CSF), osteoprotegerin (OPG), and receptor activator of nuclear factor-κB ligand (RANKL) with ELISA. Patients with PsA also had bone densitometry, plain radiographs of the hands and feet, and assessment of peripheral blood osteoclast precursors. Radiographs were scored for erosion, joint-space narrowing, osteolysis, and new bone formation.. Compared with those with psoriasis and healthy controls, patients with PsA had higher circulating concentrations of Dkk-1 and M-CSF. In patients with PsA, M-CSF and RANKL, but not Dkk-1, concentrations positively correlated with radiographic erosion, joint-space narrowing, and osteolysis scores. Mediators of bone remodeling did not correlate with the number of joints with new bone formation or with total hip-bone mineral density. Peripheral blood CD14+/CD11b+ cells, and the number of osteoclast-like cells and resorptive pits after culture with RANKL and M-CSF also correlated with radiographic damage scores. Circulating M-CSF concentrations correlated with the percentage of peripheral blood CD14+/CD11b+ cells.. Systemic expression of soluble factors that promote osteoclastogenesis is disordered in patients with PsA and may contribute to periarticular bone loss in this disease.

Topics: Adult; Aged; Arthritis, Psoriatic; Biomarkers; Bone and Bones; Bone Remodeling; Female; Humans; Intercellular Signaling Peptides and Proteins; Macrophage Colony-Stimulating Factor; Male; Middle Aged; Osteoclasts; Osteoprotegerin; RANK Ligand; Stem Cells; Young Adult

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy with a well recognized propensity for aggressive bone erosions. In some individuals, however, periarticular bone mineralization is maintained, and there is often associated new bone formation with periostitis and frank ankylosis; thus PsA manifests, in different individuals, reciprocal patterns of joint pathology suggesting a disorder of bone remodeling. Recent key scientific advances will be briefly reviewed including T cell, B cell, human leukocyte antigen associations; and the importance of neoangiogenesis, vascularity, and adhesion molecules in conjunction with inflammatory infiltrates and cytokine expression. Finally, the mechanisms of abnormal bone remodeling are discussed, including mediators of osteoclastogenesis such as RANK ligand and molecular signaling pathways including Dickkop-1 and bone morphogenetic proteins. Although much has been learned about the pathogenesis of PsA, much remains to be defined regarding the mechanisms linking synovial biology and immunopathology to different disease outcomes. Identifying key differentiating factors between the diverse PsA phenotypes, correlating findings with the rapidly advancing field of ultrasound image acquisition, and delineating the cellular and molecular mechanisms of abnormal bone remodeling in combination should enable the development of improved prognostic algorithms. This in turn should facilitate the targeting of expensive (about pound10k/patient/year) and potentially toxic yet effective biologics to patients most in need.

Topics: Arthritis, Psoriatic; Bone Remodeling; Humans; Intercellular Signaling Peptides and Proteins; Neovascularization, Pathologic; Osteoprotegerin; RANK Ligand; Synovial Membrane

The degree of bone loss in patients with psoriatic arthritis (PsA) has not been well-defined. We tested the hypothesis, whether serum levels of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), a pro-apoptotic cytokine and osteoprotegerin (OPG), an anti-osteoclastic cytokine, are associated with changes in biochemical markers of bone turnover or bone mineral density (BMD) in patients with PsA.. In a cross-sectional study, we evaluated biochemical markers of bone turnover, BMD and serum levels of TRAIL and OPG in 116 patients with PsA (mean age: 52+/-13 yrs).. In patients with PsA, osteopenia was present in one-third of women and men, while osteoporosis was more frequent in men (10.2%) than in women (1.75%). Serum levels of TRAIL were significantly higher in patients with PsA (66.1+/-45.3 pmol/l) compared with controls (50.0+/-20.1 pmol/l, P<0.01), whereas OPG serum levels were not different. There were no associations between TRAIL or OPG serum levels with BMD and biochemical markers of bone turnover. However, TRAIL serum levels were associated with C-reactive protein (CRP) levels (R = 0.201, P<0.05), whereas OPG serum levels were associated with the erythrocyte sedimentation rate (R=0.215, P<0.05).. In summary, BMD is decreased in one-third of patients with PsA, and predominantly men with PsA suffer from osteoporosis. While TRAIL serum levels are increased in PsA and correlated with CRP levels, neither TRAIL nor OPG serum levels are correlated with BMD or markers of bone metabolism.

Topics: Absorptiometry, Photon; Adult; Aged; Arthritis, Psoriatic; Biomarkers; Blood Sedimentation; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Female; Humans; Male; Middle Aged; Osteoporosis; Osteoprotegerin; Statistics, Nonparametric; TNF-Related Apoptosis-Inducing Ligand

Psoriatic arthritis (PsA) is an inflammatory joint disease characterized by extensive bone resorption. The mechanisms underlying this matrix loss have not been elucidated. We report here that blood samples from PsA patients, particularly those with bone erosions visible on plain radiographs, exhibit a marked increase in osteoclast precursors (OCPs) compared with those from healthy controls. Moreover, PsA PBMCs readily formed osteoclasts in vitro without exogenous receptor activator of NF-kappaB ligand (RANKL) or MCSF. Both osteoprotegerin (OPG) and anti-TNF antibodies inhibited osteoclast formation. Additionally, cultured PsA PBMCs spontaneously secreted higher levels of TNF-alpha than did healthy controls. In vivo, OCP frequency declined substantially in PsA patients following treatment with anti-TNF agents. Immunohistochemical analysis of subchondral bone and synovium revealed RANK-positive perivascular mononuclear cells and osteoclasts in PsA specimens. RANKL expression was dramatically upregulated in the synovial lining layer, while OPG immunostaining was restricted to the endothelium. These results suggest a model for understanding the pathogenesis of aggressive bone erosions in PsA. OCPs arise from TNF-alpha-activated PBMCs that migrate to the inflamed synovium and subchondral bone, where they are exposed to unopposed RANKL and TNF-alpha. This leads to osteoclastogenesis at the erosion front and in subchondral bone, resulting in a bidirectional assault on psoriatic bone.

Topics: Arthritis, Psoriatic; Bone Resorption; Carrier Proteins; Glycoproteins; Humans; Membrane Glycoproteins; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Stem Cells; Tumor Necrosis Factor-alpha

To test if markers of bone metabolism are altered in patients with seronegative spondyloarthropathies (SSpA).. We studied biochemical markers of bone resorption and bone formation, osteoprotegerin (OPG), and bone mineral density (BMD) in patients with psoriatic arthritis (PsA), ankylosing spondylitis (AS), and reactive arthritis (ReA) and healthy volunteers.. The bone resorption markers urinary deoxypyridinoline and crosslinked telopeptide of collagen-I were significantly increased in patients with AS, PsA, and ReA; in PsA they correlated with the acute phase response (C-reactive protein and erythrocyte sedimentation rate). The bone formation markers were divergent: bone-specific alkaline phosphatase was increased in PsA, but not in AS or ReA. Osteocalcin levels were only elevated in AS. Serum levels of OPG were significantly increased in both AS and PsA. Dual energy x-ray absorptiometry (DEXA) measurements of lumbar spine and femoral neck revealed osteopenia in patients with AS, whereas the DEXA distribution was within normal range in PsA.. Our data indicate high and, particularly in AS, unbalanced bone turnover in SSpA, consistent with the decrease in BMD found in patients with AS.

Topics: Absorptiometry, Photon; Adolescent; Adult; Aged; Amino Acids; Arthritis, Psoriatic; Arthritis, Reactive; Biomarkers; Bone Density; Bone Resorption; Cohort Studies; Female; Glycoproteins; Humans; Male; Middle Aged; Osteocalcin; Osteoprotegerin; Probability; Prognosis; Prohibitins; Prospective Studies; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Spondylitis, Ankylosing; Tumor Necrosis Factor-alpha