Osteoporosis In Ankylosing Spondylitis Research Articles

CX3CL1 promotes M1 macrophage polarization and osteoclast differentiation through NF-κB signaling pathway in ankylosing spondylitis in vitro.

Ankylosing spondylitis (AS) is an autoimmune disease with a genetic correlation and is characterized by inflammation in the axial skeleton and sacroiliac joints. Many AS patients also have inflammatory bowel diseases (IBD), but the underlying causes of intestinal inflammation and osteoporosis in AS are not well understood. CX3CL1, a protein involved in inflammation, has been found to be up-regulated in AS patients and AS-model mice. The authors investigated the effects of CX3CL1 on AS by studying its impact on macrophage polarization, inflammation factors, and osteoclast differentiation. Furthermore, the effects of inhibiting the NF-κB pathway and blocking CX3CL1 were assessed using BAY-117082 and anti-CX3CL1 mAb, respectively. AS model mice were used to evaluate the effects of anti-CX3CL1 mAb on limb thickness, spine rupture, and intestinal tissue damage. The authors found that CX3CL1 increased the expression of M1-type macrophage markers and inflammation factors, and promoted osteoclast differentiation. This effect was mediated through the NF-κB signaling pathway. Inhibition of the NF-κB pathway prevented M1-type macrophage polarization, reduced inflammation levels, and inhibited osteoclast differentiation. Injection of anti-CX3CL1 mAb alleviated limb thickness, spine rupture, and intestinal tissue damage in AS model mice by inhibiting M1-type macrophage polarization and reducing intestinal tissue inflammation. The study demonstrated that up-regulated CX3CL1 promotes M1-type macrophage polarization and osteoclast differentiation through the NF-κB signaling pathway. Inhibition of this pathway and blocking CX3CL1 can alleviate inflammation and bone destruction in AS. These findings contribute to a better understanding of the pathogenesis of AS and provide a basis for clinical diagnosis and treatment.

Exosomes derived from microRNA-21 overexpressed adipose tissue-derived mesenchymal stem cells alleviate spine osteoporosis in ankylosing spondylitis mice.

MicroRNA-21 (miR-21) can induce proliferation and differentiation of mesenchymal stem cells (MSCs) to promote bone formation, we therefore aimed to investigate whether exosomes derived from miR-21 overexpressing adipose tissue-derived MSCs (AD-MSCs) could improve spine osteoporosis in ankylosing spondylitis (AS) mice. Cultured AD-MSCs were transfected with lentivirus vectors containing miR-21 or control vector, and the supernatant was centrifugated and filtrated to harvest the exosomes (miR-21-Exos or vector-Exos). BALB/c mice were immunized with cartilage proteoglycan to establish proteoglycan-induced ankylosing spondylitis (PGIA) model. Six weeks later, PGIA mice were further injected with miR-21-Exos or vector-Exos. Transfection of miR-21 in AD-MSCs significantly enhanced miR-21 levels in AD-MSCs and their exosomes. miR-21-Exos showed concentration-dependent protective effect against spine osteoporosis in PGIA mice, evidenced by increased bone mineral content and bone mineral density, reduced number of osteoclasts, decreased content of deoxypyridinoline in the urine, decreased content of tartrate-resistant acid phosphatase (TRACP)-5b and cathepsin K in the serum, and down-regulated interleukin (IL)-6 expression in the spine, whereas vector-Exos did not show any treatment benefit. The above findings indicate that miR-21-Exos could be utilized to treat spine osteoporosis in AS.

Gender-specific SBNO2 and VPS13B as a potential driver of osteoporosis development in male ankylosing spondylitis

Osteoporosis (OP) is common in men with ankylosing spondylitis (AS). The specific pathogenesis of OP in AS, however, is still unclear. The present study attempted to identify potential genes associated with the development of OP in males with AS. Gene expression profiles were downloaded from the GSE73754 and GSE35959 datasets from the Gene Expression Omnibus (GEO). Data from OsteoporosAtlas were downloaded as a supplement. Differentially expressed genes (DEGs) were determined with the limma package. The overlapping DEGs between male AS-related genes and OP-related genes were determined. The DEGs were validated by qRT-PCR in the blood samples of males with AS. Weighted gene co-expression network analysis (WGCNA) was utilized to establish a co-expression network to identify the hub genes. A total of 17 overlapping DEGs were identified; 6 genes in 17 overlapping DEGs were verified as the essential genes in the pathogenesis of OP in male AS by qRT-PCR analysis. After WGCNA, the modules of MEblue (> 0.6) and MEred (> 0.8) were screened out by the correlation analysis and were determined to function mainly in MAPK signaling pathway and osteoclast differentiation. Analysis of the two modules revealed VPS13B and SBNO2 as key genes due to the high degree of correlation. Both genes play an important role in bone metabolism regulation in male AS. Two hub genes MYD88 in MEblue and NCK1 in MEred with high degree of connectivity were selected. Gender-specific SBNO2 and VPS13B may be key genes involved in OP in male AS.

Severity of Sacroiliitis and Erythrocyte Sedimentation Rate are Associated with a Low Trabecular Bone Score in Young Male Patients with Ankylosing Spondylitis.

To examine factors related to a low trabecular bone score (TBS) and the association between TBS and vertebral fractures in patients with ankylosing spondylitis (AS). One hundred patients (all male, aged < 50 yrs) who fulfilled the modified New York criteria for the classification of AS were enrolled. The TBS and bone mineral density (BMD) were assessed using dual-energy X-ray absorptiometry. Clinical variables, inflammatory markers, and the presence of vertebral fractures were also assessed. Sacroiliitis grade and spinal structural damage were measured using the modified New York criteria and the Stoke Ankylosing Spondylitis Spine Score (SASSS). The mean TBS was 1.38 ± 0.13. The TBS showed a positive correlation with BMD at the lumbar spine, femoral neck, and total hip. TBS negatively correlated with SASSS, whereas BMD at the lumbar spine showed a positive correlation. A significant decrease in TBS values was observed in patients with spinal structural damage (p = 0.001). Univariate analysis identified disease duration, erythrocyte sedimentation rate (ESR), sacroiliitis grade, and SASSS as being associated with TBS. Multivariate analysis identified ESR and sacroiliitis grade as being independently associated with TBS (p = 0.006 and p < 0.001, respectively). Ten patients had morphometric vertebral fractures. The mean TBS was lower in patients with vertebral fractures than in age-matched patients without fractures (p = 0.028). Lower TBS predicted vertebral fractures (area under curve = 0.733, cutoff = 1.311). The TBS in young male patients with AS is associated with the ESR and severity of sacroiliitis. The TBS may be useful as a tool for assessing osteoporosis in AS.

DOES BONE MINERAL DENSITY CHANGE IN EARLY AXIAL SPONDYLOARTHRITIS?

The rate of osteoporosis (OP) and the mechanism of its development in patients with ankylosing spondylitis (AS) and other spondyloarthrititides (SpA) have not been sufficiently investigated. Steady-state inflammatory disease activity is anticipated to be the leading factor of OP in AS. Objective: to investigate lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) in patients with early axial SpA (axSpA) and to reveal its association with inflammatory disease activity. Subjects and methods. A total of 150 patients (59 men and 91 women) aged 18 to 45 years with inflammatory back pain for ≥3 months and ≤5 years were examined. The diagnosis of axSpA was established in accordance with the 2009 ASAS criteria. BASDAI and ASDAS-CRP were used to assess activity and functional status was evaluated with BASFI. The examination included determination of HLA-B27, X-ray of the pelvis and LS, magnetic resonance imaging (MRI) of the sacroiliac joints, LS, and hip joints (in the presence of clinical signs of their involvement), and densitometry of LS (LI–IV) and FN. By taking into account the patients’ young age, the Z score was used to estimate BMD. The Z-score -2 SD or lower in at the least one of the regions examined is considered to be diminished BMD. Results and discussion. The median Z-score was -0.7 [-1.3; -0.2] SD for FN and -0.9 [-1.6; -0.6] SD for LS. Reduced BMD in at the least one of the regions examined was diagnosed in 27 (18.0%) patients. There was lower BMD in LS in 21 (14.0%) patients and in FN in 8 (5.3%). Two (1.3%) patients were diagnosed as having osteopenia in the two examined regions. There was no association between diminished BMD and age, gender, disease activity assessed with BASDAI, ASDAS-СRP, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). An association was found between inflammatory LS changes, as evidenced by MRI (MRI spondylitis), and reduced BMD in at least one of the examined regions. MRI spondylitis was detected in 27 (18.0%) patients. Decreased BMD in any of the examined skeletal regions was seen in 9 (33.3%) of the 27 patients having MRI spondylitis; the remaining 18 (66.7%) patients had normal BMD values. In the absence of MRI spondylitis, osteopenia was identified in 18 (14.6%) patients; normal BMD values were noted in 105 (85.4%); p = 0.03). There was also a relationship between the presence of MRI spondylitis and diminished BMD in the same region. LS osteopenia was found in 7 (25.9%) patients with MRI spondylitis and LS BMD remained within the normal range in 20 (74.1%). In the absence of MRI spondylitis, LS osteopenia was observed in 14 (11.4%) patients and LS BMD was normal in 109 (88.6%) (p < 0.05). Conclusion. There was an association between inflammatory LS changes, as evidenced by MRI, and reduced BMD in the same region. Our findings confirm the hypothesis that bone mass loss in the vertebral bodies in early axSpA results from local inflammation.

Higher Level of Dickkopf-1 is Associated with Low Bone Mineral Density and Higher Prevalence of Vertebral Fractures in Patients with Ankylosing Spondylitis.

Patients with ankylosing spondylitis (AS) have an increased risk of bone loss and vertebral fractures. In this study, we explored the hypothesis that the excess bone loss and vertebral fractures might be related with the activity of the Wingless signaling pathway, and in particular with the serum levels of its circulating inhibitors, Sclerostin and Dickkopf-1 (DKK1). We recruited 71 patients diagnosed with AS. Lateral radiographs of the total spine were analyzed to detect the presence of vertebral fractures, and bone mineral density (BMD) was assessed in all patients using dual X-ray absorptiometry at lumbar spine and proximal femoral site. Blood samples were obtained and levels of C-reactive protein (CRP), DKK1, and Sclerostin were measured. Blood samples from 71 healthy sex- and age-matched volunteers were collected to be used as controls. Vertebral fractures were detected more commonly among men than in women (29 vs 8%, respectively). DKK1, but not Sclerostin serum levels, were inversely correlated to lumbar spine Z-score BMD. Patients with one or more prevalent vertebral fractures had significantly higher DKK1 levels, without significant difference in Sclerostin serum levels. A significant positive correlation was found between DKK1 serum levels and CRP (r=0.240, p=0.043). The association we found between serum DKK1 levels and BMD values and vertebral fracture prevalence suggests that DKK1 might contribute to the severity of osteoporosis in AS.

Comparison of proliferation and differentiation of osteoblasts derived from vertebral body and lamina in patients with thoracolumbar kyphosis secondary to Ankylosing Spondylitis

Background Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease. Osteoporosis is a common feature of AS, with a prevalence of 19% to 62%. Previous studies have indicated the increase of osteoclast activity responsible for the development of osteoporosis in AS. However, to our best knowledge, the osteogenic activities of osteoblasts in AS has never been addressed before. Therefore, the objective of this study was to investigate the proliferation and differentiation of osteoblasts derived from the vertebral body and lamina in AS patients and to compare the differences of osteoblast activities between AS and age-matched controls.

Osteoporosis and vertebral fractures in ankylosing spondylitis

To review the recent literature on the prevalence of osteoporosis, risk of vertebral fractures, and the recent advances in the treatment of osteoporosis in patients with ankylosing spondylitis (AS). Newer data suggest that the prevalence of osteoporosis is 25% and vertebral fractures is 10% in patients with AS. New advances in the field of osteoimmunology help explain the trabecular bone loss and generalized osteoporosis linked to increased expression of receptor activator of nuclear factor kappa B ligand (RANK-L) due to pro-inflammatory cytokines, and the simultaneous new bone formation (e.g. syndesmophytes) in areas of previous inflammation through suppressed Dickkopf-related protein 1 levels and increased WNT (wingless) signaling. Osteoporosis is a common problem for patients with AS. We recommend screening within 10 years of diagnosis. Suspecting and promptly recognizing vertebral fractures in patients with AS could prevent serious neurological complications. Although bisphosphonates and tumor necrosis factor-α inhibitors look promising, further prospective trials on the treatment of osteoporosis in AS are needed.

Bone mineral density in young males with ankylosing spondylitis

To assess bone mineral density (BMD) abnormalities in young Indian males with ankylosing spondylitis (AS) and factors influencing this. Eighty AS male subjects were compared with 160 age/sex matched controls for BMD of lumbar spine and proximal femur. AS subjects were evaluated and followed up every 3 months for disease activity. BMD was estimated at spine and proximal femur using the dual-energy X-ray absorptiometry (DXA) technique. All subjects were males with mean age of 32.9 ± 8.3 years and mean duration of disease was 8.1 ± 5.8 years. AS subjects had significantly lower BMD at the spine and femur as compared with controls (both P < 0.001). Using WHO standards, osteoporosis (OP) in spine and femur neck was seen in 28.75% (controls: 1.84%, P < 0.001) and 11.54% (controls: 1.23%, P < 0.001), respectively. No statistically significant difference in prevalence of OP was seen with disease duration, C-reactive protein levels and disease activity indices (all P > 0.05). Syndesmophytes were seen in 22.5% (n = 18) of AS subjects. There was no significant difference between BMD values at spine in AS subjects with or without syndesmophytes (0.91 + 0.16 g/cm(2) vs. 0.90 + 0.14 g/cm(2), P = 0.79). OP is a significant complication in AS even in young males with early disease, and more prevalent in the spine compared to femur. In our study, BMD was not influenced by disease activity indices, inflammatory markers or total disease duration. Spinal BMD is the most sensitive site for defining OP in AS.

Osteoporosis in Ankylosing Spondylitis

Osteoporosis (OP) is a frequent complication of ankylosing spondylitis (AS), even in early stages of the disease, and is associated with elevated levels of biochemical markers of bone turnover, proinflammatory cytokines, and acute-phase reactants. This suggests that systemic inflammatory mediators, such as interleukin-6 and tumor necrosis factor-alpha, may be involved. Various factors that conceivably work in conjunction with one another also cause bone loss in AS (eg, genetic polymorphisms of vitamin D, low levels of osteoprotegerin and sex steroid hormones, and impaired calcium and vitamin D absorption). Dual x-ray absorptiometry for assessing bone mineral density (BMD) has limitations in patients with AS because of unreliability of spinal measurements, particularly in advanced disease with new bone formation. Femoral neck BMD is reduced and correlates with increased risk of vertebral fractures. Hence, measurement of BMD at the femoral neck may provide the most accurate means of detecting osteopenia and OP and could assess fracture risk in AS patients. No guidelines are available for detection and treatment of OP in AS, and most patients are young men, who are less likely to be screened. The only evidence-based recommendation is that optimal control of disease activity in AS prevents bone loss. A recent study showed a beneficial effect of infliximab therapy on bone turnover markers and BMD in AS. Also, bisphosphonates may be useful in managing OP in AS.

Elevated serum levels of soluble receptor activator of nuclear factors- B ligand (sRANKL) and reduced bone mineral density in patients with ankylosing spondylitis (AS)

To assess bone mineral density (BMD), serum levels of soluble receptor activator of nuclear factors-kappaB ligand (sRANKL) and osteoprotegerin (OPG) in patients with ankylosing spondylitis (AS), and to determine their relationships with disease activities. Serum levels of sRANKL and OPG in AS were measured by sandwich enzyme-linked immunosorbent assay. The disease activities were determined using Bath Ankylosing Spondylitis Disease Activity Score Index, Bath Ankylosing Spondylitis Functional Index , Bath Ankylosing Spondylitis Metrology Index and Bath Ankylosing Spondylitis Patient Global Score. BMD of femur and lumbar spine was measured by dual energy X-ray absorptiometry. Radiological grading was determined by New York criteria for sacroiliitis and modified Stoke Ankylosing Spondylitis Spine Score. Osteoporosis and osteopaenia of femoral neck were found in 33 and 41% of patients, respectively. BMD of femoral neck showed negative correlation with disease activity indexes, erythrocyte sedimentation rate and C-reactive protein. The serum sRANKL levels and the ratio of sRANKL to OPG were significantly higher in patients with AS than those of controls. The sRANKL/OPG ratio tended to increase in patients with reduced BMD and radiological findings of active inflammation. About 74% of AS patients have reduced BMD and this change reflects disease activity. Serum sRANKL levels and sRANKL/OPG ratios are up-regulated in patients with AS and have relationship with BMD and radiological changes. These results suggest that the imbalance between RANKL and OPG might be involved in the pathogenesis and clinical courses of osteoporosis in AS.

Collagen breakdown in ankylosing spondylitis-relationship to disease related parameters

Patients with ankylosing spondylitis (AS) often develop osteoporosis particularly of the axis skeleton. To investigate disease-related or therapeutic influence on bone catabolism, we quantified the total excretion of the collagen crosslinks (CL) pyridinoline (Pyd) and deoxypyridinoline (Dpyd) in 91 AS patients (26 f, 65 m) in relation to disease activity or stage and therapy with NSAID. CL were determined by HPLC (High Performance Liquid Chromatography). The AS patients show a highly significant positive correlation between Pyd and the inflammatory activity (CrP, r = 0.36, p < 0.001: ESR, r = 0.379, p < 0.001). Also the quotient Pyd/Dpyd correlates positively to the inflammatory activity (CrP, r = 0.262, p < 0.001: ESR, r = 0.325, p < 0.002). In the case of increased inflammatory disease activity (CrP > or = 10 mg/l vs CrP < 10 mg/l or ESR > or = 10 30 mm vs ESR < 30 mm), Pyd excretion is raised significantly (p < 0.042 for CrP and p < 0.009 for ESR). Among those patients treated with NSAID therapy, significantly reduced levels for Dpyd (p < 0.001) and raised levels for the quotient Pyd/Dpyd (p < 0.002) appear. In the case of advanced radiological changes with evidence of syndesmophytes, Pyd (p = 0.014) and Dpyd (p < 0.004) were significantly raised in urine. Regarding the movement function (finger-floor distance, schober test), no significant correlation to crosslink excretion could be proven. From our investigations, we assume that osteoporosis in AS is primarily caused by an inflammatory-mediated degradation of bone.

Relationship between disease activity and serum levels of vitamin D metabolites and parathyroid hormone in ankylosing spondylitis.

Vertebral fractures due to osteoporosis are a common but frequently unrecognized complication of ankylosing spondylitis (AS) and various factors may contribute to the development of osteoporosis in AS. It is known that inflammatory activity in rheumatic disease (i.e., proinflammatory cytokines) itself plays a possible role in the pathophysiology of bone loss. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) seems to be another possible candidate for mediatory function in regulating both the inflammatory process and bone turnover. The aim of this study was to evaluate the relation between disease activity, bone turnover and calciotropic hormones. In 70 patients with established AS and an age- and sex-matched control group, the relation between disease activity (erythrocyte sedimentation rate, C-reactive protein, Bath Ankylosing Spondylitis Disease Activity Index), and serum levels of vitamin D metabolites, parathyroid hormone (PTH), bone alkaline phosphatase (bAP) and urinary pyridinium cross-links were determined. Serum levels of 1,25(OH)2D3 (p<0.01) and PTH (p<0.01) were negatively correlated with disease activity, the excretion of urinary pyridinium crosslinks showed a positive correlation with disease activity (p<0.01), and 1,25(OH)2D3 and PTH were positively correlated with bAP (p<0.01). These results indicate that high disease activity in AS is associated with an alteration in vitamin D metabolism and increased bone resorption. Furthermore, the decreased levels of 1,25(OH)2D3 may contribute to a negative calcium balance and inhibition of bone formation. Our results suggest further research is necessary to determine whether low levels of 1,25(OH)2D3 as an endogenous immune modulator suppressing activated T cells and cell proliferation may accelerate the inflammation process in AS.