Pathomechanisms of bone loss in rheumatoid arthritis.
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ABSTRACT:
SUBMITTER: Sakthiswary R
PROVIDER: S-EPMC9428319 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Pathomechanisms of bone loss in rheumatoid arthritis.
Sakthiswary Rajalingham R Uma Veshaaliini Rajeswaran R Chin Kok-Yong KY Das Srijit S Sirasanagandla Srinivasa Rao SR
Frontiers in medicine 20220817
Rheumatoid arthritis (RA) is an autoimmune disease, in which the inflammatory processes involve the skeletal system and there is marked destruction of the bones and the surrounding structures. In this review, we discuss the current concepts of osteoimmunology in RA, which represent the molecular crosstalk between the immune and skeletal systems, resulting in the disruption of bone remodeling. Bone loss in RA can be focal or generalized, leading to secondary osteoporosis. We have summarized the r ...[more]
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Project description:ObjectiveT-cells are critical players in the pathogenesis of osteoporosis in patients with rheumatoid arthritis (RA). Premature senescence of lymphocytes including the accumulation of senescent CD4+ T-cells is a hallmark feature of RA. Whether T-cell senescence is associated with bone loss in RA patients is elusive so far.MethodsThis includes a prospective study of consecutive patients with RA (n = 107), patients with primary osteopenia/-porosis (n = 75), and healthy individuals (n = 38). Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry scan. Flow cytometry, magnetic-associated cell sorting, and cell culture experiments were performed to analyze the pro-osteoclastic phenotype and the function of senescent CD4+CD28- T-cells.ResultsPatients with osteopenia/-porosis yielded a higher prevalence of senescent CD4+CD28- T-cells than individuals with normal BMD, in the RA, as well as in the non-RA cohort. Receptor activator of nuclear factor kappa-B ligand (RANKL) was expressed at higher levels on CD4+CD28- T-cells as compared to CD28+ T-cells. Stimulation with interleukin-15 led to an up-regulation of RANKL expression, particularly on CD28- T-cells. CD4+CD28- T-cells induced osteoclastogenesis more efficiently than CD28+ T-cells.ConclusionOur data indicate that senescent T-cells promote osteoclastogenesis more efficiently than conventional CD28+ T-cells, which might contribute to the pathogenesis of systemic bone loss in RA and primary osteoporosis.
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Project description:ObjectiveTo evaluate the effectiveness of bazedoxifene in preventing bone loss in patients with rheumatoid arthritis (RA) receiving low-dose glucocorticoids (GCs).MethodsIn this randomized, controlled, open-label study, we assigned postmenopausal women with osteopenia who had been receiving low-dose GCs for RA to two groups: a group receiving bazedoxifene (20 mg/day) with elemental calcium 1200 mg and vitamin D 800 IU daily (bazedoxifene group) and a group receiving the same doses of calcium and vitamin D only (control group). As primary outcome, bone mineral density (BMD) change in the lumbar spine (L-spine) from baseline to 48 weeks was assessed. Changes in BMD in the femur, trabecular bone score, bone turnover markers, and development of fracture were assessed as secondary outcomes. For intention-to-treat analysis, 20 completed data sets were created by applying multiple imputations by chained equations.ResultsA total of 114 patients (57 patients in each group) were recruited. A significant increase in L-spine BMD (0.015 g/cm2, P = 0.007) was observed in the bazedoxifene group, and the increase was significantly higher than in the control group (0.013, 95% CI 0.0003-0.026, P = 0.047). Reductions in bone turnover markers in the bazedoxifene group were significantly greater than in the control group. Only one fracture was observed in the bazedoxifene group, while four fractures developed in the control group.ConclusionIn postmenopausal patients with RA receiving low-dose GCs, bazedoxifene improved BMD and reduced bone turnover markers. However, the change in BMD did not exceed the least significant change.Trial registrationClinicalTrials.gov, NCT02602704 .
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Project description:Rheumatoid arthritis (RA) is an autoimmune chronic connective tissue disease that produces persistent systemic inflammation, with joint inflammation leading to function loss and joint destruction. Low bone mass causes skeletal bone loss, commonly referred to as osteopenia or osteoporosis. We conducted this literature review to examine the relationship between RA and osteoporosis and the variables contributing to this connection. We used articles from the US National Library of Medicine (PubMed), Google Scholar, Science Direct to access the required information. Eventually, our results concluded that RA could result in local periarticular and generalized bone loss. Many risk factors contribute to this association, such as chronic joints inflammation, glucocorticoid use, genetics, and estrogen hormone effects. Still, it is not clear yet whether this is due to a consequence of treatment, immobility, or the activity of the disease. There are many recommendations by the American College of Rheumatology for RA patients during the disease course to reduce the risk of osteoporosis development, which include early starts of disease-modifying anti-inflammatory drugs (DMARDs), doing a dual-energy x-ray (DXA) or quantitative ultrasound (QUS) for identifying a patient at risk of osteoporosis, taking vitamin D, calcium, and bisphosphonates. Further prospective studies and clinical trials are essential to provide a solid evidence-based recommendation that will help to prevent bone loss in RA patients.
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Project description:BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by disrupted bone homeostasis. This study investigated the effect and underlying mechanisms of one-carbon metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) on osteoclast differentiation and bone loss in RA.MethodsThe expression of MTHFD2 was examined in CD14 + monocytes and murine bone marrow-derived macrophages (BMMs). RNA-sequencing was performed to evaluate the regulatory mechanisms of MTHFD2 on osteoclastogenesis. Extracellular flux assay, JC-1 staining, and transmission electron microscopy were used to detect mitochondrial function and energy metabolism changes during osteoclast formation. Collagen-induced arthritis (CIA) mice were used to evaluate the therapeutic effect of MTHFD2 knockdown on bone loss. Bone volume and osteoclast counts were quantified by μCT and histomorphometry.ResultsElevated MTHFD2 was observed in RA patients and CIA mice with a positive correlation to bone resorption parameters. During osteoclast formation, MTHFD2 was significantly upregulated in both human CD14 + monocytes and murine BMMs. The application of MTHFD2 inhibitor and MTHFD2 knockdown suppressed osteoclastogenesis, while MTHFD2 overexpression promoted osteoclast differentiation in vitro. RNA-sequencing revealed that MTHFD2 inhibition blocked oxidative phosphorylation (OXPHOS) in osteoclasts, leading to decreased adenosine triphosphate (ATP) production and mitochondrial membrane potential without affecting mitochondrial biogenesis. Mechanistically, inhibition of MTHFD2 downregulated the expression of mitochondrial creatine kinase 1 (CKMT1), which in turn affected phosphocreatine energy shuttle and OXPHOS during osteoclastogenesis. Further, a therapeutic strategy to knock down MTHFD2 in knee joint in vivo ameliorated bone loss in CIA mice.ConclusionsOur findings demonstrate that MTHFD2 is upregulated in RA with relation to joint destruction. MTHFD2 promotes osteoclast differentiation and arthritic bone erosion by enhancing mitochondrial energy metabolism through CKMT1. Thus, targeting MTHFD2 may provide a potential new therapeutic strategy for tackling osteoclastogenesis and bone loss in RA.
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Project description:ObjectivesRheumatoid arthritis (RA) is an independent risk factor of osteoporosis. However, if disease activity is successfully controlled using the treat-to-target (T2T) strategy, the risk of bone mineral density (BMD) loss can be diminished. We evaluated if RA is a risk factor even when the T2T is applied in clinical cases.MethodsFrom September 2017 to August 2019, 741 patients were examined using dual-energy X-ray absorptiometry; of these, 279 were diagnosed with RA who attained clinical remission within 6 months (RA-rem) and 53 could not attain clinical remission (RA-nonrem), while 409 were not diagnosed with RA (non-RA). The following characteristics between RA-rem and non-RA were matched using the propensity score matching (PSM) technique: age, sex, past bone fragility fracture experience, osteoporosis drug intervention ratio, glucocorticoid administration ratio, mean dose, Barthel Index score, body mass index, serum-creatinine-to-cystatin C ratio, and the number of comorbidities. The BMDs and changes of the lumbar spine, femoral neck, total hip, and greater trochanter were statistically compared between the RA-rem and the non-RA after PSM, and between RA-nonrem and RA-rem after PSM using the Mann-Whitney U test.ResultsIn total, 107 patients of RA-rem and 108 of non-RA were recruited. BMDs and changes of every part demonstrated no significant differences between the 2 groups. BMDs in every part of RA-rem after PSM were significantly greater than those in every part of RA-nonrem, while no significant difference in change during follow-up.ConclusionsIf disease activity is controlled in clinical remission, RA will not contribute to BMD reduction.
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Project description:The purpose of this prospective study is to compare the Chinese visceral adiposity index (CVAI) between early rheumatoid arthritis (ERA) patients and healthy controls; and to assess the relationship between CVAI and the bone microstructure using high-resolution peripheral quantitative computed tomography (HR-pQCT) in ERA patients. 104 female ERA and 100 age-, gender- and BMI-matched healthy controls were recruited for the comparison of CVAI. All ERA patients were prospectively followed for 1 year. HR-pQCT scan of the distal radius, tibia and second metacarpal head were performed at baseline and after one-year. ERA patients were divided into two sub-groups according to the median CVAI value (65.73) (low CVAI and high CVAI groups). CVAI in the ERA group was significantly higher than the controls group (p = 0.01). At baseline, the high CVAI group had a higher ESR level (p = 0.004) while the cortical volumetric bone mineral density (vBMD) was lower (at both the distal radius and tibia, all p < 0.05) compared to the low CVAI group. Linear regression analysis revealed that a higher baseline CVAI was an independent predictor of a lower cortical vBMD at month 12 (distal radius: B = - 0.626, p = 0.022, 95%CI - 1.914 to - 0.153; tibia: B = - 0.394, p = 0.003, 95%CI - 1.366 to - 0.290); and a greater reduction in trabecular vBMD (tibia: B = 0.444, p = 0.001, 95%CI 0.018-0.063; distal radius: B = 0.356, p = 0.008, 95%CI 0.403-0.063). In summary, CVAI is an independent predictor of trabecular bone loss in female patients with ERA, which may be augmented by a chronic inflammatory state in patients with visceral dysfunction of fat metabolism.Trial registration: http://Clinicaltrial.gov no: NCT01768923, 16/01/2013.
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Project description:BackgroundTo explore the prevalence of bone loss among patients with rheumatoid arthritis (RA) and healthy controls (HC) and further explored the risk factors for osteopenia and osteoporosis of RA patients.MethodsA cross-sectional survey was undertaken in four hospitals in different districts in South China to reveal the prevalence of bone loss in patients. Case records, laboratory tests, and bone mineral density (BMD) results of patients were collected. Traditional multivariable logistic regression analysis and two machine learning methods, including least absolute shrinkage selection operator (LASSO) and random forest (RF) were for exploring the risk factors for osteopenia or osteoporosis in RA patients.ResultsFour hundred five patients with RA and 198 HC were included. RA patients had lower BMD in almost BMD measurement sites than healthy controls; the decline of lumbar spine BMD was earlier than HC. RA patients were more likely to comorbid with osteopenia and osteoporosis (p for trend < 0.001) in the lumbar spine than HC. Higher serum 25-hydroxyvitamin D3 level and using tumor necrosis factor inhibitor in the last year were protective factors; aging, lower body mass index, and increased serum uric acid might be risk factors for bone loss.ConclusionsRA patients were more prone and earlier to have bone loss than HC. More attention should be paid to measuring BMD in RA patients aging with lower BMI or hyperuricemia. Besides, serum vitamin D and all three measurement sites are recommended to check routinely. TNFi usage in the last year might benefit bone mass.
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