Systemic Bone Loss Research Articles

Punicalagin ameliorates collagen-induced arthritis by downregulating M1 macrophage and pyroptosis via NF-κB signaling pathway.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that eventually leads to disability. Inflammatory cell infiltration, severe joint breaking and systemic bone loss are the main clinical symptoms. In this study, we established a collagen-induced arthritis (CIA) model and found a large number of M1 macrophages and pyroptosis, which are important sources of proinflammatory cytokines. Punicalagin (PUN) is an active substance extracted from pomegranate peel. We found that it inhibited joint inflammation, cartilage damage and systemic bone destruction in CIA mice. PUN effectively alleviated the high expression of inflammatory cytokines in synovial tissue in vivo. PUN treatment shifted macrophages from the M1 phenotype to the M2 phenotype after stimulation with lipopolysaccharide (LPS) and interferon (IFN)-γ. The expression of inducible nitric oxide synthase (iNOS) and other proinflammatory cytokines released by M1 macrophages was decreased in the PUN treatment group. However, simultaneously, the expression of markers of anti-inflammatory M2 macrophages, such as arginase (Arg)-1 and interleukin (IL)-10, was increased. In addition, PUN treatment attenuated pyroptosis by downregulating the expression of NLRP3 and caspase-1, thereby preventing inflammatory cell death resulting from the release of IL-1β and IL-18. Mechanistically, PUN inhibited the activation of receptor activators of the nuclear factor-κB (NF-κB) signaling pathway, which contributes to M1 polarization and pyroptosis of macrophages. We concluded that PUN ameliorated pathological inflammation by inhibiting M1 phenotype polarization and pyroptosis and has great potential as a therapeutic treatment for human RA.

Bone Loss and Radiographic Damage Profile in Rheumatoid Arthritis Moroccan Patients.

BackgroundRheumatoid arthritis (RA) is a known cause of joint destruction and systemic bone loss. In this study, we aimed to evaluate the bone damage and bone loss profiles of established RA patients.MethodsWe designed a cross-sectional study on a cohort of established RA patients. The bone evaluation was performed by obtaining standard X-ray images of hands and feet combined with bone mineral density (BMD) measurements. Radiographic joint damage was calculated by the modified total Sharp /van der Heijde score (mTSS). BMD was obtained by performing dual energy X-ray absorptiometry of the lumbar spine and femoral neck. Data on age, smoking, alcoholism, steroid prescription, body mass index (BMI), disease duration, disease activity, and functional disability were collected.ResultsA total of 93 RA patients were recruited. Their mean age was 51.59±12.38 years, with a mean disease duration of 12.07±9.19 years. A total of 36.6% of patients had osteoporosis, and the mean mTSS was 70.33±48.93. Both hip (P=0.0005) and lumbar BMD (P=0.0005) were correlated with mTSS. Backward regression analyses determined that bone damage was associated with high titers of rheumatoid factor, low lumbar BMD, and low BMI. General bone loss was associated with gender, steroid dose, steroid duration, menopause, and BMI.ConclusionsBone damage was associated with low BMI and axial bone loss in our RA population.

Infliximab prevents systemic bone loss and suppresses tendon inflammation in a collagen-induced arthritis rat model.

Reduced Bone Mineral Density (BMD) and tendon abnormalities, such as tenosynovitis and enthesitis, are prevalent comorbidities in patients with rheumatoid arthritis (RA). The aim of the present study was to investigate the effect of chronic treatment with infliximab on BMD and tendon inflammation in an animal model of inflammatory arthritis. Collagen-Induced Arthritis (CIA) was induced in rats, followed by long-term intraperitoneal administration of infliximab. Two additional groups of animals received methotrexate either as a monotherapy or as a co-treatment to infliximab. BMD was evaluated by Micro-Computed Tomography (Micro-CT) and bone histological examination. Tendon inflammation was assessed histologically and by quantitative ELISA analysis of pro-inflammatory cytokines in tendon tissues. Both methotrexate and infliximab treatment alleviated joint inflammation and reduced paw edema. Infliximab-treated animals exhibited an improved trabecular microarchitecture on micro-CT and histological analysis compared to both non-treated and methotrexate-treated animals. Infliximab almost reversed the pathological changes in tendons induced by CIA. Finally, we observed statistically significant declines in tendon TNF-a and IL-23 levels after infliximab treatment. Our study provides evidence that infliximab prevents arthritis-related osteoporosis and suppresses tendon inflammation in an animal model of inflammatory arthritis, in addition to controlling disease activity. These findings offer perspectives for the management of osteoporosis and enthesitis in RA.

Single-stage revision for the infected total knee arthroplasty : the Cardiff experience.

AimsPeriprosthetic joint infection (PJI) is a devastating complication following total knee arthroplasty (TKA). Two-stage revision has traditionally been considered the gold standard of treatment for established infection, but increasing evidence is emerging in support of one-stage exchange for selected patients. The objective of this study was to determine the outcomes of single-stage revision TKA for PJI, with mid-term follow-up.MethodsA total of 84 patients, with a mean age of 68 years (36 to 92), underwent single-stage revision TKA for confirmed PJI at a single institution between 2006 and 2016. In all, 37 patients (44%) were treated for an infected primary TKA, while the majority presented with infected revisions: 31 had undergone one previous revision (36.9%) and 16 had multiple prior revisions (19.1%). Contraindications to single-stage exchange included systemic sepsis, extensive bone or soft-tissue loss, extensor mechanism failure, or if primary wound closure was unlikely to be achievable. Patients were not excluded for culture-negative PJI or the presence of a sinus.ResultsOverall, 76 patients (90.5%) were infection-free at a mean follow-up of seven years, with eight reinfections (9.5%). Culture-negative PJI was not associated with a higher reinfection rate (p = 0.343). However, there was a significantly higher rate of recurrence in patients with polymicrobial infections (p = 0.003). The mean Oxford Knee Score (OKS) improved from 18.7 (SD 8.7) preoperatively to 33.8 (SD 9.7) at six months postoperatively (p < 0.001). The Kaplan-Meier implant survival rate for all causes of reoperation, including reinfection and aseptic failure, was 95.2% at one year (95% confidence interval (CI) 87.7 to 98.2), 83.5% at five years (95% CI 73.2 to 90.3), and 78.9% at 12 years (95% CI 66.8 to 87.2).ConclusionOne-stage exchange, using a strict debridement protocol and multidisciplinary input, is an effective treatment option for the infected TKA. This is the largest single-surgeon series of consecutive cases reported to date, with broad inclusion criteria.Cite this article: Bone Jt Open 2021;2(5):305–313.

Gamabufotalin Inhibits Osteoclastgenesis and Counteracts Estrogen-Deficient Bone Loss in Mice by Suppressing RANKL-Induced NF-κB and ERK/MAPK Pathways.

Osteolytic bone disease is a condition of imbalanced bone homeostasis, characterized mainly by excessive bone-resorptive activity, which could predispose these populations, such as the old and postmenopausal women, to developing high risk of skeletal fragility and fracture. The nature of bone homeostasis is the coordination between the osteoblasts (OBs) and osteoclasts (OCs). Abnormal activation of osteoclasts (OCs) could compromise the bone homeostasis, constantly followed by a clutch of osteolytic diseases, including postmenopausal osteoporosis, osteoarthritis, and rheumatoid arthritis. Thus, it is imperatively urgent to explore effective medical interventions for patients. The traditional Chinese medicine (TCM) gamabufotalin (CS-6) is a newly identified natural product from Chansu and has been utilized for oncologic therapies owing to its good clinical efficacy with less adverse events. Previous study suggested that CS-6 could be a novel anti-osteoporotic agent. Nevertheless, whether CS-6 suppresses RANK-(receptor activator of nuclear factor-κ B ligand)/TRAF6 (TNF receptor-associated factor 6)-mediated downstream signaling activation in OCs, as well as the effects of CS-6 on OC differentiation in vivo, remains elusive. Therefore, in this present study, we aimed to explore the biological effects of CS-6 on osteoclastogenesis and RANKL-induced activation of related signaling pathways, and further to examine the potential therapeutic application in estrogen-deficient bone loss in the mice model. The results of in vitro experiment showed that CS-6 can inhibit RANKL-induced OC formation and the ability of bone resorption in a dose-dependent manner at both the early and late stages of osteoclastogenesis. The gene expression of OC-related key genes such as tartrate-resistant acid phosphatase (TRAP), CTSK, DC-STAMP, MMP9, and β3 integrin was evidently reduced. In addition, CS-6 could mitigate the systemic estrogen-dependent bone loss and pro-inframammary cytokines in mice in vivo. The molecular mechanism analysis suggested that CS-6 can suppress RANKL/TRAF6-induced early activation of NF-κB and ERK/MAPK signaling pathways, which consequently suppressed the transcription activity of c-Fos and NFATc1. Taken together, this present study provided ample evidence that CS-6 has the promise to become a therapeutic candidate in treating osteolytic conditions mediated by elevated OC formation and bone resorption.

Mechanisms for increased systemic fracture risk after index fracture

The single best predictor of future fracture risk is a prior fracture at any skeletal site. However, the mechanisms underlying this relationship remain incompletely understood. Here we review three potential mechanisms underlying increased risk. An index fracture may reflect preexisting deficits in bone quality or impairments in physical function. Second, fracture may cause biomechanical changes that increase future fracture risk. Third, fracture induces a period of systemic bone loss that is never fully recovered. Further investigation into these mechanisms can inform treatments that prevent future fractures for individuals with a prior history of fracture.

Do anti-carbamylated protein antibodies in rheumatoid arthritis reflect local and systemic osteoporosis? A study of osteoprotegrin and receptor activator for nuclear factor kappa B ligand and radiological assessment

BackgroundOne of the most important and dangerous complications of rheumatoid arthritis (RA) is bone loss, which manifested by erosions and juxta-articular or systemic bone loss. Anti-carbamylated protein (anti-CarP) antibodies which are also called anti-homocitrulline antibodies have recently been found in RA. Increase anti-CarP antibody titres may lead to severe disease and increase the progression of bone loss. Osteoprotegrin and receptor activator for nuclear factor kappa B and its ligand (RANKL) are the main players in the pathogenesis of osteoporosis. Thus, we aimed to investigate and detect the presence and prevalence of anti-CarP in rheumatoid arthritis and their association with disease severity and osteoporosis, as well as with OPG/RANKL in 80 Egyptian RA patients to highlight this relationship which could be useful in managing RA patients with osteoporosis.ResultsSerum anti-CarP levels were significantly increased in the RA group compared with the control group (P< 0.001). We found a negative association between anti-CarP and anti-CCP and disease activity (r=−0.878, −0.534, respectively, P<0.001). We also found a positive correlation between anti-CarP and the Larsen score, DEXA score, RF, HAQ, and RANKL (r=0.646, 0.287, 0.243, 0.892, 0.671, 0.869 [respectively], P<0.001) and there was negative correlation between anti-CarP and OPG (r=−0.553, P<0.001).ConclusionAnti-CarP antibodies are associated with disease severity and disability in RA patients. They could play an important and significant role in the pathogenesis of osteoporosis in these patients.

Plasma cells promote osteoclastogenesis and periarticular bone loss in autoimmune arthritis.

In rheumatoid arthritis (RA), osteoclastic bone resorption causes structural joint damage as well as periarticular and systemic bone loss. Periarticular bone loss is one of the earliest indices of RA, often preceding the onset of clinical symptoms via largely unknown mechanisms. Excessive osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL) expressed by synovial fibroblasts causes joint erosion, whereas the role of RANKL expressed by lymphocytes in various types of bone damage has yet to be elucidated. In the bone marrow of arthritic mice, we found an increase in the number of RANKL-expressing plasma cells, which displayed an ability to induce osteoclastogenesis in vitro. Genetic ablation of RANKL in B-lineage cells resulted in amelioration of periarticular bone loss, but not of articular erosion or systemic bone loss, in autoimmune arthritis. We also show conclusive evidence for the critical contribution of synovial fibroblast RANKL to joint erosion in collagen-induced arthritis on the arthritogenic DBA/1J background. This study highlights the importance of plasma-cell RANKL in periarticular bone loss in arthritis and provides mechanistic insight into the early manifestation of bone lesion induced by autoimmunity.

Systemic Bone Density at Disease Onset Is Associated With Joint Erosion Progression in Early Naive to Treatment Rheumatoid Arthritis: A Prospective 12-Month Follow-Up Open-Label Study

Objectives: Osteoporosis and bone erosions are hallmarks of rheumatoid arthritis (RA) since disease onset is underpinned by the inflammatory burden. In this observational study, we aimed to dissect the putative RA-related parameters and bone-derived biomarkers associated with systemic and focal bone loss at disease onset and with their progression.Methods: One-hundred twenty-eight patients with early rheumatoid arthritis (ERA) were recruited at disease onset. At study entry, demographic, clinical, and immunological parameters were recorded. Each ERA patient underwent plain X-rays of the hands and feet at study entry and after 12 months to assess the presence of erosions. After enrollment, each patient was treated according to the recommendations for RA management and followed up based on a treat-to-target (T2T) strategy. At baseline, blood samples for soluble biomarkers were collected from each patient, and plasma levels of osteoprotegerin (OPG), receptor activator of nuclear factor κB ligand (RANKL), Dickkopf-1 (DKK1), and interleukin 6 (IL-6) were assessed by enzyme-linked immunosorbent assay (ELISA). Seventy-one ERA patients underwent bone mineral density (BMD) measurement at the left femoral neck and second to fourth lumbar spine vertebrae (L2–L4) by dual-energy X-ray absorptiometry (DXA).Results: Among the whole cohort, 34 (26.6%) ERA patients with bone erosions at study entry had a higher disease activity (p = 0.02) and IL-6 plasma levels (p = 0.03) than non-erosive ones. Moreover, at DXA, 33 (46.5%) ERA patients had osteopenia, and 16 (22.5%) had osteoporosis; patients with baseline bone erosions were more likely osteopenic/osteoporotic than non-erosive ones (p = 0.03), regardless of OPG, RANKL, and DKK1 plasma levels. Obese ERA patients were less likely osteopenic/osteoporotic than normal weight ones (p = 0.002), whereas anti-citrullinated protein antibodies (ACPA) positive ERA patients were more likely osteopenic/osteoporotic than ACPA negative ones (p = 0.034). At logistic regression analysis, baseline Disease Activity Score measured on 44 joints (DAS44) [OR: 2.46 (1.11–5.44)] and osteopenic/osteoporosis status [OR: 7.13 (1.27–39.94)] arose as independent factors of erosiveness. Baseline osteopenic/osteoporotic status and ACPA positivity were associated with bone damage progression during the follow-up.Conclusions: Bone erosions presence is associated with systemic bone loss since the earliest phases of RA, suggesting that the inflammatory burden and autoimmune biology, underpinning RA, represent crucial enhancers of bone remodeling either locally as at systemic level.

Bone erosion in the 2nd metacarpophalangeal head: association with its bone mineral density by HR-pQCT in rheumatoid arthritis patients

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease depicted by synovial inflammation leading to local and systemic bone loss. The aim of this study was to evaluate by a HR-pQCT (High Resolution Peripheral Quantitative Computed Tomography) study which parameters are associated with volume of bone erosions including bone mineral density (BMD) around erosions (VOI 1 to 4 = volume of interest), BMD of metacarpophalangeal (MCP) head, BMD of radius, presence of osteophytes and joint space width (JSW).MethodsFifty female RA patients (18–50 years) were enrolled in this study. Demographic and disease-specific data, laboratory inflammatory parameters and handgrip test were performed. All patients underwent HR-pQCT of 2nd and 3rd MCP joints and distal radius, according to established protocols. The volume of bone erosions was evaluated by MIAF (Medical Image Analysis Framework) software. Osteophytes were analyzed by manual method.ResultsThe mean of age and disease duration were 40.0 ± 6.0 yrs. and 10.8 ± 4.8 yrs., respectively. According to DAS-28 (Disease Activity Score), 54% (27) of the sample were in remission. However, when SDAI (Simplified Disease Activity Index) was used, only 18% (9) were under remission. The mean of HAQ (Health Assessment Questionnaire), ESR (Erythrocyte sedimentation rate) and CRP (C reactive protein) were 0.9 ± 0.7, 13.9 ± 12.2 mm and 5.6 ± 7.5 mg/mL, respectively. Forty-six bone erosions (0.9 ± 1.2 erosion/patient) and 14 osteophytes (0.3 ± 0.7 osteophyte/patient) were found in 2nd MCP head. The median (IQR-Interquartile range) of volume of erosion and volume of osteophytes were 14.9 (5.7;35.9)mm3 and 3.1 (2.1, 4.3)mm3, respectively. The mean of JSW was 80.5 ± 34.2 mm3. The volume of bone erosions was negatively correlated with BMD of 2nd MCP head, VOI-4 and JSW; and it was positively correlated with osteophytes number. Regarding absence or presence of erosion in 2nd MCP head, a significant difference was found between BMD of MCP head, osteophyte number and JSW. Multiple linear regression analysis showed that only BMD of 2nd MCP head was independently associated with volume of bone erosions.ConclusionBMD of MCP head was independently associated with volume of bone erosion, suggesting that this parameter should be used to analyze and monitoring bone destruction, as well as to evaluate treatment response in RA patients.

Rheumatoid Arthritis in the View of Osteoimmunology.

Rheumatoid arthritis is characterized by synovial inflammation and irreversible bone erosions, both highlighting the immense reciprocal relationship between the immune and bone systems, designed osteoimmunology two decades ago. Osteoclast-mediated resorption at the interface between synovium and bone is responsible for the articular bone erosions. The main triggers of this local bone resorption are autoantibodies directed against citrullinated proteins, as well as pro-inflammatory cytokines and the receptor activator of nuclear factor-κB ligand, that regulate both the formation and activity of the osteoclast, as well as immune cell functions. In addition, local bone loss is due to the suppression of osteoblast-mediated bone formation and repair by inflammatory cytokines. Similarly, inflammation affects systemic bone remodeling in rheumatoid arthritis with the net increase in bone resorption, leading to systemic osteoporosis. This review summarizes the substantial progress that has been made in understanding the pathophysiology of systemic and local bone loss in rheumatoid arthritis.

Fractal-Based Analysis of Bone Microstructure in Crohn’s Disease: A Pilot Study

Crohn’s disease (CD) is associated with bone loss and increased fracture risk. TX-Analyzer™ is a new fractal-based technique to evaluate bone microarchitecture based on conventional radiographs. The aim of the present study was to evaluate the TX-Analyzer™ of the thoracic and lumbar spine in CD patients and healthy controls (CO) and to correlate the parameters to standard imaging techniques. 39 CD patients and 39 age- and sex-matched CO were analyzed. Demographic parameters were comparable between CD and CO. Bone structure value (BSV), bone variance value (BVV) and bone entropy value (BEV) were measured at the vertebral bodies of T7 to L4 out of lateral radiographs. Bone mineral density (BMD) and trabecular bone score (TBS) by dual energy X-ray absorptiometry (DXA) were compared to TX parameters. BSV and BVV of the thoracic spine of CD were higher compared to controls, with no difference in BEV. Patients were further divided into subgroups according to the presence of a history of glucocorticoid treatment, disease duration > 15 years and bowel resection. BEV was significantly lower in CD patients with these prevalent risk factors, with no differences in BMD at all sites. Additionally, TBS was reduced in patients with a history of glucocorticoid treatment. Despite a not severely pronounced bone loss in this population, impaired bone quality in CD patients with well-known risk factors for systemic bone loss was assessed by TX-Analyzer™.

Effect of Single Versus Multiple Fractures on Systemic Bone Loss in Mice.

Systemic bone loss after initial fracture contributes to an increased risk of secondary fracture. Clinical research has revealed an association between the risk of future fracture and the number or magnitude of prior fractures. However, the change in systemic bone mass after single versus multiple fractures is unknown. We used ipsilateral femur and tibia fractures as multiple fractures and a femur or tibia fracture as a single fracture to investigate the influence of single versus multiple fractures on systemic bone mass. Seventy-two adult male C57BL/6J mice underwent transverse osteotomies of the ipsilateral femur and/or tibia with subsequent internal fixation. The dynamic change of in vivo whole-body BMD was assessed at 4 days, 2 weeks, and 4 weeks after fracture. The microstructure of the L5 vertebral body and contralateral femur was assessed using micro-CT (μCT) and biomechanical tests (vertebral compression test and three-point bending test) at 2 and 4 weeks. Tartrate-resistant acid phosphatase (TRAP) staining, sequential fluorescence labeling, and systemic inflammatory cytokines were also quantified. A greater decrease in whole-body BMD was observed after multiple than single fractures. The trabecular bone volume fraction, trabecular number, and trabecular thickness of the L5 vertebral body were significantly reduced. There were no significant differences in cortical thickness, trabecular bone microstructure, or bone strength in the contralateral femur. At 4 days and 2 weeks, we observed significant increases in the serum levels of IL-6 and TNF-α. We also observed an increase in the osteoclast number of the L5 vertebral body at 4 days. These data indicate that systemic bone loss might increase with the number or severity of prior fractures, and the mechanism may be partly associated with an increased osteoclast number and a more severe inflammatory response. © 2020 American Society for Bone and Mineral Research (ASBMR).

Green tea extract rich in epigallocatechin gallate impairs alveolar bone loss in ovariectomized rats with experimental periodontal disease.

Periodontal disease and osteoporosis are characterized by bone resorption, and researchers have shown an association between these two diseases through increasing loss of systemic bone mass and triggering alveolar bone loss. Green tea is a common and easily accessible beverage, and evidences show that flavonoid epigallocatechin gallate (EGCG) could decrease bone loss in pathologies such as osteoporosis and periodontal disease. In order to verify its possible effects and apply them in the treatment and prevention of these diseases, this investigation aimed to evaluate the influence of green tea extract (GTE) on bone metabolism of ovariectomized rats after experimental periodontal disease (EPD) by histological, morphological and microtomographic parameters. Wistar female rats were divided into Sham, Sham+EPD, Sham+EPD+GTE, OVX, OVX+EPD and OVX+EPD+GTE groups. Immediately after surgery, gavage administration of 50mg/kg of green tea extract (GTE) was performed for 60days, with subsequent induction of periodontal disease by ligature 15days before euthanasia. Mandible and femur samples were collected for histological, morphometric and microtomographic analysis. The results were analysed by means of statistical software with significance set at 5%. Histological and morphometric analysis showed a significant decrease in alveolar and femoral trabecular bone loss in groups that received GTE. Microtomographic results showed that trabecular thickness and bone surface density values in alveolar bone interradicular septum of the OVX+EPD+GTE groups were similar to the Sham group. The results obtained suggest that green tea extract may improve bone metabolism in osteoporotic rats with periodontal disease.

Getting to the heart of bone loss

Heart attack leads to systemic bone loss in mice, indicating fracture risk as a clinical comorbidity of heart attack.

Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis

BackgroundThe transmembrane-TNF transgenic mouse, TgA86, has been shown to develop spontaneously peripheral arthritis with signs of axial involvement. To assess similarity to human spondyloarthritis, we performed detailed characterization of the axial, peripheral, and comorbid pathologies of this model.MethodsTgA86 bone pathologies were assessed at different ages using CT imaging of the spine, tail vertebrae, and hind limbs and characterized in detail by histopathological and immunohistochemical analysis. Cardiac function was examined by echocardiography and electrocardiography and bone structural parameters by μCT analysis. The response of TgA86 mice to either early or late anti-TNF treatment was evaluated clinically, histopathologically, and by μCT analysis.ResultsTgA86 mice developed with 100% penetrance spontaneous axial and peripheral pathology which progressed with time and manifested as reduced body weight and body length, kyphosis, tail bendings, as well as swollen and distorted hind joints. Whole-body CT analysis at advanced ages revealed bone erosions of sacral and caudal vertebrae as well as of sacroiliac joints and hind limbs and, also, new ectopic bone formation and eventually vertebral fusion. The pathology of these mice highly resembled that of SpA patients, as it evolved through an early inflammatory phase, evident as enthesitis and synovitis in the affected joints, characterized by mesenchymal cell accumulation, and neutrophilic infiltration. Subsequently, regression of inflammation was accompanied by ectopic bone formation, leading to ankylosis. In addition, both systemic bone loss and comorbid heart valve pathology were evident. Importantly, early anti-TNF treatment, similar to clinical treatment protocols, significantly reduced the inflammatory phase of both the axial and peripheral pathology of TgA86 mice.ConclusionsThe TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the role of transmembrane TNF in the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease.

Systemic bone loss following myocardial infarction in mice.

Myocardial infarction (MI) and osteoporotic fracture are leading causes of morbidity and mortality, and epidemiological evidence linking their incidence suggests possible crosstalk. MI can exacerbate atherosclerosis through the sympathetic nervous system (SNS) activation and β3 adrenoreceptor-mediated release of hematopoietic stem cells, leading to monocytosis. We hypothesized that this same pathway initiates systemic bone loss following MI,since osteoclasts differentiate from monocytes. In this study, MI was created with left anterior descendingartery ligation in 12-week-old male mice (n = 24) randomized to β3 -adrenergic receptor (AR) antagonist (SR 59230A) treatment or no treatment for 10 days postoperatively. Additional mice (n = 21, treated and untreated) served as unoperated controls. Bone mineral density (BMD), bone mineral content (BMC), and body composition were quantified at baseline and 10 days post-MI using dual-energy x-ray absorptiometry; circulating monocyte levels were quantified and the L5 vertebral body and femur were analyzed with microcomputed tomography 10 days post-MI. We found that MI led to circulating monocyte levels increases, BMD and BMC decreases at the femur and lumbar spine in MI mice (-6.9% femur BMD, -3.5% lumbar BMD), and trabecular bone volume decreases in MI mice compared with control mice. β3 -AR antagonist treatment appeared to diminish the bone loss response (-5.3% femur BMD, -1.2% lumbar BMD), though these results were somewhat inconsistent. Clinical significance:These results suggest that MI leads to systemic bone loss, but that the SNS may not be a primary modulator of this response; bone loss and increased fracture risk may be important clinical comorbidities following MI or other ischemic injuries.

Anti-carbamylated protein antibodies in premenopausal rheumatoid arthritis women: relation to disease activity and bone loss.

Anti-carbamylated protein antibodies (anti-CarP Abs) are present in patients with RA, however, their association with bone loss is not confirmed. The purpose of this study was to determine the relation between the serum level of anti-CarP Abs in premenopausal RA women and disease activity and bone loss. This case-control study was conducted on 48 premenopausal women with RA and 48 matched healthy premenopausal women. All RA women were subjected to clinical examination, disease activity assessment using the 28-joint DAS (DAS28) and Clinical Disease Activity Index (CDAI), functional assessment using the HAQ, physical activity assessment using the International Physical Activity Questionnaire (IPAQ), fatigue assessment using the Modified Fatigue Impact Scale (MFIS), serological tests as well as anti-CarP Abs using ELISA. Moreover, the BMD was measured by DXA and plain X-ray of both hands was done to assess juxta-articular osteopenia and erosions. The anti-CarP Abs level was significantly higher in RA patients than in healthy controls. The serum level of anti-CarP Abs had a significant positive correlation with the RA DAS28, CDAI, HAQ, MFIS and original Sharp score, while a significant negative correlation was present with the IPAQ. Anti-CarP Abs were negatively correlated with either spine BMD or Z-score and positively correlated with the original Sharp score. Anti-CarP Abs were higher in premenopausal RA women compared with older and BMI matched healthy women. Anti-CarP Abs are associated with higher RA disease activity, increased disability and fatigability and decreased physical activity. Moreover, anti-CarP Abs are associated with systemic trabecular bone loss as well as local bone loss.

Cherubism as a systemic skeletal disease: evidence from an aggressive case

BackgroundCherubism is a rare autosomal dominant genetic condition caused by mutations in the SH3BP2 gene. This disease is characterized by osteolysis of the jaws, with the bone replaced by soft tissue rich in fibroblasts and multinuclear giant cells. SH3BP2 is a ubiquitous adaptor protein yet the consequences of SH3BP2 mutation have so far been described as impacting only face. Cherubism mouse models have been generated and unlike human patients, the knock-in mice exhibit systemic bone loss together with a systemic inflammation.Case presentationIn light of these observations, we decided to search for a systemic cherubism phenotype in a 6-year-old girl with an aggressive cherubism. We report here the first case of cherubism with systemic manifestations. Bone densitometry showed low overall bone density (total body Z-score = − 4.6 SD). Several markers of bone remodelling (CTx, BALP, P1NP) as well as inflammation (TNFα and IL-1) were elevated. A causative second-site mutation in other genes known to influence bone density was ruled out by sequencing a panel of such genes.ConclusionsIf this systemic skeletal cherubism phenotype should be confirmed, it would simplify the treatment of severe cherubism patients and allay reservations about applying a systemic treatment such as those recently published (tacrolimus or imatinib) to a disease heretofore believed to be localised to the jaws.

Region-dependent bone loss in the lumbar spine following femoral fracture in mice.

We previously showed that after femur fracture, mice lose bone at distant skeletal sites, including the lumbar vertebrae. This bone loss may increase the risk of subsequent vertebral fractures, particularly if bone is lost from high-strain bone regions, which are most commonly found adjacent to the superior and inferior endplates of the vertebral body. To determine regional bone loss from the lumbar spine following femur fracture, we evaluated the cranial, center, and caudal portions of the L5 vertebral bodies of Young (3month-old) and Middle-Aged (12month-old) female C57BL/6 mice two weeks after a transverse femur fractures compared to Young and Middle-Aged uninjured control mice. We hypothesized that greater bone loss would be observed in the cranial and caudal regions than in the center region in both Young and Middle-Aged mice. Trabecular and cortical bone microstructure were evaluated using micro-computed tomography, and osteoclast number and eroded surface were evaluated histologically. In Young Mice, fracture led to decreased trabecular and cortical bone microstructure primarily in the cranial and caudal regions, but not the center region, while Middle-Aged mice demonstrated decreases in trabecular bone in all regions, but did not exhibit any changes in cortical bone microstructure after fracture. No significant differences in osteoclast number or eroded surface were observed at this time point. These data suggest that bone loss following fracture in Young Mice is concentrated in areas that contain a large amount of high-strain tissue, whereas bone loss in Middle-Aged mice is less region-dependent and is restricted to the trabecular bone compartment. These results illustrate how systemic bone loss after fracture could lead to decreases in vertebral strength, and how distinct regional patterns and age-dependent differences in bone loss may differentially affect vertebral fracture risk.