Bone Erosion In Rheumatoid Arthritis Research Articles

Prediction model for bone erosion in rheumatoid arthritis based on musculoskeletal ultrasound and clinical risk factors.

Progressive bone erosion (BE) is a prominent manifestation of structural damage in rheumatoid arthritis (RA). This study aimed to construct and validate a BE prediction model (BEPM) for RA based on musculoskeletal ultrasound and clinical risk factors. A total of 312 RA patients without BE were consecutively collected and followed up for 2years, who were divided into BE group and non-bone erosion group, as confirmed by two radiology experts based on at least two imaging techniques. Relevant clinical information, such as anti-cyclic citrullinated peptide (ACCP) antibody and disease duration, was collected. Musculoskeletal ultrasound examinations were performed on all patients upon admission. Univariate and binary logistic regression analyses were conducted to identify risk factors for BE and to establish the prediction model. The calibration, diagnostic efficacy, and clinical effectiveness of BEPM were evaluated by calibration curve plots, receiver-operating characteristic curve, and decision curve analysis (DCA). Binary logistic regression analysis screened four variables, including synovial hyperplasia, synovial blood flow, ACCP + , and disease duration, into the prediction model. BEPM exhibited good diagnostic performance in both the training and validation groups, with area under the curve values of 0.949 (95% CI 0.924-0.973) and 0.965 (95% CI 0.935-0.996), respectively. Using 0.376 as the optical cutoff value for BE, the sensitivity, specificity, and Youden index of the model in the training group were 86.0%, 90.4%, and 76.4%, respectively. In the DCA curves, BEPM indicated overall good population benefit. BEPM demonstrates high diagnostic performance and clinical utility, and may be a useful clinical model for predicting BE in patients with RA. Key Points • Synovial hyperplasia, synovial blood flow, ACCP+ , and disease duration are independent risk factors for bone erosion in RA patients. • BEPM exhibits good diagnostic performance in both the training and validation groups. • Combining musculoskeletal ultrasound parameters with key clinical risk factors to construct a bone erosion model is feasible.

Targeting BRD4 to attenuate RANKL-induced osteoclast activation and bone erosion in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that can cause destruction of cartilage and bone's extracellular matrix. Bromodomain 4 (BRD4), as a transcriptional and epigenetic regulator, plays a key role in cancer and inflammatory diseases. While, the role of BRD4 in bone destruction in RA has not been extensively reported. Our study aimed to investigate the effect of BRD4 on the bone destruction in RA and, further, its mechanism in the pathogenesis of the disease. In this study, receiving approval from the Ethical Committee of the Affiliated Hospital of Qingdao University, we evaluated synovial tissues from patients with RA and OA for BRD4 expression through advanced techniques such as immunohistochemistry, quantitative real-time PCR (qRT-PCR), and Western blotting. We employed a collagen-induced arthritis (CIA) mouse model to assess the therapeutic efficacy of the BRD4 inhibitor JQ1 on disease progression and bone destruction, supported by detailed clinical scoring and histological examinations. Further, in vitro osteoclastogenesis assays using RAW264.7 macrophages, facilitated by TRAP staining and resorption pit assays, provided insights into the mechanistic effects of JQ1 on osteoclast function. Statistical analysis was rigorously conducted using SPSS, applying Kruskal-Wallis, one-way ANOVA, and Student's t-tests to validate the data. In our study, we found that BRD4 expression significantly increased in the synovial tissues of RA patients and the ankle joints of CIA mice, with JQ1, a BRD4 inhibitor, effectively reducing inflammation, arthritis severity (p < 0.05), and bone erosion. Treatment with JQ1 not only improved bone mass and structural integrity in CIA mice but also downregulated osteoclast-related gene expression and the RANKL/RANK signaling pathway, indicating a suppression of osteolysis. Furthermore, in vitro assays demonstrated that JQ1 markedly inhibited osteoclast differentiation and function, underscoring the pivotal role of BRD4 in osteoclastogenesis and its potential as a target for therapeutic intervention in RA-induced bone destruction. Our study concludes that targeting BRD4 with the inhibitor JQ1 significantly mitigates inflammation and bone destruction in rheumatoid arthritis, suggesting that inhibition of BRD4 may be a potential therapeutic strategy for the treatment of bone destruction in RA.

Contribution of Musculoskeletal Ultrasound in the Diagnosis of Seronegative Rheumatoid Arthritis.

This is a study to investigate the value of musculoskeletal ultrasound for the early diagnosis of seronegative rheumatoid arthritis (SNRA); and to study the relationship between anti-cyclic citrullinated peptide antibody (anti-CCP) and the occurrence of bone erosion in rheumatoid arthritis (RA) detected by ultrasound. A total of 101 patients with RA or osteoarthritis (OA) admitted to the First Affiliated Hospital of Anhui Medical University from July 2022 to December 2023 were selected and divided into the SNRA group, the SPRA group, and the OA group. The patients' metacarpophalangeal joints, proximal interphalangeal joints, distal interphalangeal joints, and wrist joints of both hands were ultrasonically examined separately, and the extensor tendon, flexor tendon, synovium, joint surface, joint cavity, and bone surface were observed. The differences in the detection of joint effusion, bone erosion, and joint space narrowing were not statistically significant between SNRA group and OA group (P > .05), the differences in the detection of synovitis and tenosynovitis were statistically significant (P < .05). The mean levels of synovial hyperplasia grade and synovial blood flow grade between SNRA group and OA group were significantly different (P < .05). The differences in synovitis, tenosynovitis, joint effusion, and joint space narrowing were not statistically significant between SNRA and SPRA groups (P > .05), and the differences in bone erosion were statistically significant (P < .05). The mean levels of synovial hyperplasia grade and synovial blood flow grade between SNRA group and SPRA group were significantly different (P < .05). Logistic regression analysis showed that anti-CCP antibody was an influential factor for bone erosion in RA patients (P < .05). The ROC curve was plotted, and the optimal cut-off value of anti-CCP antibody was 356.5U/mL, at which time the AUC was 0.716, the sensitivity of diagnosing bone erosion was 0.714, the specificity was 0.694, and the Yoden index was 0.408. In summary, ultrasound is helpful for the early diagnosis of SNRA by evaluating the condition of joints, synovium, and tendon sheath, and when anti-CCP antibodies are positive, ultrasound is more likely to detect bone erosion. Ultrasound examination combined with anti-CCP antibody can further observe the joint lesions.

An Injectable Hydrogel Composing Anti-Inflammatory and Osteogenic Therapy toward Bone Erosions Microenvironment Remodeling in Rheumatoid Arthritis.

Healing bone erosions in rheumatoid arthritis (RA) remains greatly challenging via biomaterial strategies. Given the unsuccessful innate bone erosion healing due to an inflammatory disorder, over-activated osteoclasts, and impaired osteoblasts differentiation, RA pathogenesis-guided engineering of an innovative hydrogel platform is needed for remodeling osteoimmune and osteogenic microenvironment of bone erosion healing. Herein, in situ adaptable and injectable interpenetrating polymer network (IPN) hydrogel is developed through an ingenious combination of a bio-orthogonal reaction between hyaluronic acid (HA) and collagen, along with effective electrostatic interactions leveraging bisphosphonate (BP)-functionalized HA macromers (HABP) and nanorod shaped zinc (Zn)-doped biphasic calcium phosphate (ZnBCP). IPN hydrogel exhibits exceptional adaptability to the local shape complexity at bone erosions, and by integrating ZnBCP and HABP, a multi-stage releasing platform is engineered, facilitating controlled cargo delivery for remodeling more anti-inflammatory M2 cells and reducing over-activated osteoclastic activities, thereby reconstructing the bone regeneration microenvironment. Sustainedly co-delivering multiple ions (calcium and phosphate) can display excellent osteogenic properties and be conducive to the bone formation process, by effects of osteogenesis-associated cell differentiation. Overall, the introduced bioactive IPN hydrogel therapy remodels the osteoimmune environment by synergistic pro-inflammation-resolving, osteogenesis, and anti-osteoclastic activities, displaying excellent bone reconstruction in the collagen-induced arthritis rabbit model.

Deletion of RANKL in regulatory T cells ameliorates bone erosion in arthritis

Abstract Rheumatoid arthritis (RA) is an autoimmune disease that leads to bone erosion mediated through osteoclasts.Osteoclast differentiation is promoted through engagement of RANK by its ligand (RANKL) expressed by multiple lineages. Whereas regulatory T cells (Tregs) typically suppress osteoclastogenesis, Tregs developing in a pro-inflammatory environment can express RANKL and promote osteoclast function (Levescot et al.2021).To test the importance of osteoclastogenic Tregs in vivo, we developed a mouse selectively lacking RANKL expression in Tregs (FoxP3YFP/creRANKLflox/flox, hereafter RANKLΔTreg). Arthritis was induced by administration of K/BxN serum containing arthritogenic IgG antibodies. Joint inflammation and synovial neutrophil infiltration in RANKLΔTreg mice were similar to WT animals. Compared with Tregs from lymph nodes, Tregs from inflamed joints exhibited increased expression of activation markers including CD25,Foxp3,CD44, and CTLA4, without a difference between RANKLΔTreg and WT animals; RANKLΔTreg mice exhibited a trend for higher Treg PD-1 expression. In WT mice, the percentage of Tregs expressing RANKL was elevated in synovial fluid compared to lymph nodes. Correspondingly, microCT showed a significant reduction in bone erosion in RANKLΔTreg compared to WT mice (p=0.003). These findings are consistent with a pathogenic role of RANKL-expressing Treg for RA bone erosion in arthritis; whether RANKL impacts other Treg functions remains to be established.

Osteoimmunology: The Crosstalk between T Cells, B Cells, and Osteoclasts in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an ongoing inflammatory condition that affects the joints and can lead to severe damage to cartilage and bones, resulting in significant disability. This condition occurs when the immune system becomes overactive, causing osteoclasts, cells responsible for breaking down bone, to become more active than necessary, leading to bone breakdown. RA disrupts the equilibrium between osteoclasts and osteoblasts, resulting in serious complications such as localized bone erosion, weakened bones surrounding the joints, and even widespread osteoporosis. Antibodies against the receptor activator of nuclear factor-κB ligand (RANKL), a crucial stimulator of osteoclast differentiation, have shown great effectiveness both in laboratory settings and actual patient cases. Researchers are increasingly focusing on osteoclasts as significant contributors to bone erosion in RA. Given that RA involves an overactive immune system, T cells and B cells play a pivotal role by intensifying the immune response. The imbalance between Th17 cells and Treg cells, premature aging of T cells, and excessive production of antibodies by B cells not only exacerbate inflammation but also accelerate bone destruction. Understanding the connection between the immune system and osteoclasts is crucial for comprehending the impact of RA on bone health. By delving into the immune mechanisms that lead to joint damage, exploring the interactions between the immune system and osteoclasts, and investigating new biomarkers for RA, we can significantly improve early diagnosis, treatment, and prognosis of this condition.

Interleukin 6 and Bone Erosions in Rheumatoid Arthritis in an African Hospital

Interleukin 6 and Bone Erosions in Rheumatoid Arthritis in an African Hospital

RhoA Promotes Synovial Proliferation and Bone Erosion in Rheumatoid Arthritis through Wnt/PCP Pathway.

Ras homolog gene family member A (RhoA) plays a major role in the Wnt/planar cell polarity (PCP) pathway, which is significantly activated in patients with rheumatoid arthritis (RA). The function of RhoA in RA synovitis and bone erosion is still elusive. Here, we not only explored the impact of RhoA on the proliferation and invasion of RA fibroblast-like synoviocytes (FLSs) but also elucidated its effect on mouse osteoclast and a mouse model of collagen-induced arthritis (CIA). Results showed that RhoA was overexpressed in RA and CIA synovial tissues. Lentivirus-mediated silencing of RhoA increased apoptosis, attenuated invasion, and dramatically upregulated osteoprotegerin/receptor activator of nuclear factor-κB ligand (OPG/RANKL) ratio in RA-FLSs. Additionally, the silencing of RhoA inhibited mouse osteoclast differentiation in vitro and alleviated synovial hyperplasia and bone erosion in the CIA mouse model. These effects in RA-FLSs and osteoclasts were all regulated by RhoA/Rho-associated protein kinase 2 (ROCK2) and might interact with Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways.

Transcriptomic characterization of classical monocytes highlights the involvement of immuno-inflammation in bone erosion in Rheumatoid Arthritis.

Evidence-based data suggest that under inflammatory conditions, classical monocytes are the main source of osteoclasts and might be involved in bone erosion pathophysiology. Here, we analyze the transcriptomic profile of classical monocytes in erosive and non-erosive rheumatoid arthritis patients in order to better understand their contribution to bone erosion. Thirty-nine premenopausal RA patients were consecutively enrolled and divided into two groups based on the presence of bone erosions on hand joints. Classical monocytes were isolated from peripheral blood through negative selection, and RNA-seq was performed using a poly-A enrichment kit and Illumina® platform. Classical monocytes transcriptome from healthy age-matched women were also included to identify differentially expressed genes (DEGs). Therefore, gene sets analysis was performed to identify the enriched biological pathways. RNA-seq analysis resulted in the identification of 1,140 DEGs of which 89 were up-regulated and 1,051 down-regulated in RA patients with bone erosion compared to those without bone erosions. Among up-regulated genes, there was a highlighted expression of IL18RAP and KLF14 related to the production of pro-inflammatory cytokines, innate and adaptive immune response. Genes related to collagen metabolism (LARP6) and bone formation process (PAPPA) were down-regulated in RA patients with erosions. Enriched pathways in patients with erosions were associated with greater activation of immune activation, and inflammation. Interestingly, pathways associated with osteoblast differentiation and regulation of Wnt signaling were less activated in RA patients with erosions. These findings suggest that alterations in expression of monocyte genes related to the inflammatory process and impairment of bone formation might have an important role in the pathophysiology of bone erosions in RA patients.

Neutrophil extracellular traps mediate bone erosion in rheumatoid arthritis by enhancing RANKL-induced osteoclastogenesis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that can cause bone erosion due to increased osteoclastogenesis. Neutrophils involvement in osteoclastogenesis remains uncertain. Given that neutrophil extracellular traps (NETs) can act as inflammatory mediators in rheumatoid arthritis, we investigated the role of NETs in stimulating bone loss by potentiating osteoclastogenesis during arthritis. The level of NETs in synovial fluid from arthritis patients was assessed. Bone loss was evaluated by histology and micro-CT in antigen-induced arthritis (AIA)-induced WT mice treated with DNase or in Padi4-deficient mice (Padi4flox/flox LysMCRE ). The size and function of osteoclasts and the levels of RANKL and osteoprotegerin (OPG) released by osteoblasts that were incubated with NETs were measured. The expression of osteoclastogenic marker genes and protein levels were evaluated by qPCR and western blotting. To assess the participation of TLR4 and TLR9 in osteoclastogenesis, cells from Tlr4-/- and Tlr9-/- mice were cultured with NETs. Rheumatoid arthritis patients had higher levels of NETs in synovial fluid than osteoarthritis patients, which correlated with increased levels of RANKL/OPG. Moreover, patients with bone erosion had higher levels of NETs. Inhibiting NETs with DNase or Padi4 deletion alleviated bone loss in arthritic mice. Consistently, NETs enhanced RANKL-induced osteoclastogenesis that was dependent on TLR4 and TLR9 and increased osteoclast resorptive functions in vitro. In addition, NETs stimulated the release of RANKL and inhibited osteoprotegerin in osteoblasts, favouring osteoclastogenesis. Inhibiting NETs could be an alternative strategy to reduce bone erosion in arthritis patients.

Genetic polymorphisms of rs73620203 in the transforming growth interacting factor gene associated with rheumatoid arthritis in a Chinese population

ObjectiveTo explore the association of single nucleotide polymorphisms (SNPs) in the transforming growth interacting factor (TGIF) gene with bone metabolism markers and rheumatoid arthritis (RA) susceptibility. MethodsThree SNPs were genotyped in 155 RA patients and 168 healthy controls using high-resolution melting (HRM) analysis. The serum levels of osteocalcin, bone alkaline phosphatase (BALP), and β type I collagen-crosslinked C telopeptide (β-CTX) were detected using electrochemical luminescence in 108 patients randomly selected from the RA group. ResultsGenotype and allele frequency analysis showed that rs73620203 was associated with bone erosion in RA (P = 0.012 and P = 0.003, respectively), and individuals carrying the T allele for rs73620203 showed a decreased RA risk (OR = 0.59, 95% CI = 0.42–0.84; P = 0.003). In sex-specific analysis, the rs73620203 polymorphism was associated with susceptibility to RA in women (P = 0.022 and P = 0.006, respectively). In addition, RA patients with three genotypes at the rs73620203 locus showed significant differences in serum osteocalcin and BALP (P = 0.006 and P = 0.037, respectively). Haplotype analysis revealed that the haploid ATG and GCA frequencies were significantly lower in the RA group (P = 0.036, OR = 0.693; P = 0.002, OR = 0.189, respectively), while the haploid ACA frequency of the RA group was enhanced (P < 0.01, OR = 5.058). ConclusionOur study provides the first evidence that rs73620203 is associated with RA susceptibility and the relationship between TGIF gene SNPs and the regulation of bone metabolism in RA patients.

Melittin acupoint injection in attenuating bone erosion in collagen-induced arthritis mice via inhibition of the RANKL/NF-κB signaling pathway.

Rheumatoid arthritis (RA) is an autoimmune disease leading to chronic joint inflammation. Bone erosion is the most serious pathological condition of RA and the main cause of joint deformities and disability. Melittin acupoint injection (MAI) is an effective traditional Chinese medicine (TCM) method for RA treatment. This study aimed to investigate the effect of MAI on RA bone erosion and to elucidate the underlying mechanism. A collagen-induced arthritis (CIA) mouse model was established as the experimental subject. MAI was administrated once every other day for 28 days to mice with CIA. The effects of MAI on joint diseases were assessed by body weight, arthritis index (AI) score, swollen joint count (SJC) score, and hind paw thickness. Ankle radiological changes were captured by micro-computed tomography (micro-CT) and histological changes were observed by pathological staining. Organ histological changes, spleen index, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine (Crea) levels of serum were tested to evaluate the toxicity of MAI. Cytokine expression levels were confirmed by enzyme-linked immunosorbent assay (ELISA) to evaluate the immunity of CIA mice. MAI administration markedly improved the clinical signs of CIA in mice, including hind paw thickness, AI, and the number of swollen paw joints (most of them P<0.05 or even <0.01). According to histopathological analysis, MAI ameliorated inflammatory cell infiltration, synovial hyperplasia, pannus formation, and bone erosion (all P<0.01). Micro-CT and tartrate-resistant acid phosphatase (TRAP) staining (P<0.01) also revealed that MAI could relieve bone erosion via reducing the formation of osteoclasts. Not only could MAI relieve the immunological boost [P<0.05 for the high-dose MAI (HM) group], but also it had no liver or kidney side effects (P>0.05). In addition, it decreased the serum levels of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) and increased the serum levels of IL-4 and IL-10 (the majority of P<0.05 or even <0.01). Transcriptome sequencing results indicated that MAI affected the expression of osteoclast differentiation pathway genes, which was connected with the receptor activator of the nuclear factor κB ligand/nuclear factor kappa B (RANKL/NF-κB) pathway. Based on our findings, MAI could suppress joint inflammation and inhibit RANKL/NF-κB-mediated osteoclast differentiation to rescue bone erosion in CIA mice, suggesting that MAI can be a potentially therapeutic substance for RA.

Role of denosumab in bone erosions in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammation and synovitis which evolve into joint destruction and deformity. Bone abnormalities are represented by marginal bone erosions and iuxta-articular and generalized osteoporosis. Overactivation of osteoclasts along with dysregulation of osteoblasts are the key events. Bone resorption is mediated by the receptor activator of nuclear factor (NF)-κB (RANK) ligand (RANK-L), responsible for the differentiation, proliferation, and activation of osteoclasts. RANK-L binds its receptor RANK, localized on the surface of preosteoclasts and mature osteoclasts promoting osteoclastogenesis. High levels of RANK-L were demonstrated in active RA patients. Denosumab, a fully human monoclonal antibody, binds RANK-L and suppresses the RANK-RANK-L signaling pathway leading to the inhibition of osteoclastogenesis. A retrospective analysis of published studies such as clinical trials evidenced the efficacy of denosumab in preventing bone erosion progression in RA patients. Key messages Key questions to answer in future include the following: Could denosumab be associated with other biologic therapies in RA patients? Could denosumab block the progression of bone damage in RA? Could denosumab be used for the prevention of bone erosion in RA?

The Influence of Adipokines on Radiographic Damage in Inflammatory Rheumatic Diseases

Inflammatory rheumatic diseases (IRDs) are complex immune-mediated diseases that are characterized by chronic inflammation of the joints. Rheumatoid arthritis (RA) and spondyloarthritis (SpA), including axial SpA (ax SpA) and psoriatic arthritis (PsA), are the most common forms of IRD. Both RA and ax SpA are characterized by a chronic course with progressive structural modifications, namely, cartilage damage and bone erosions in RA and osteoproliferative changes with spinal ossifications in ax SpA. The adipose tissue is involved in the pathophysiology of IRDs via the release of several proteins, namely, adipokines. Several adipokines with pro-inflammatory effects have been identified, such as leptin, adiponectin, visfatin and resistin. In this review, we discuss the role that adipokines may play in the structural modifications of the peripheral joints and/or axial skeleton. In RA, the role of leptin in structural damage remains controversial, while adiponectin and its high-molecular-weight isoform are known to have an influence on the development of bone erosions and radiographic progression. Resistin also appears to be a potent detrimental adipokine for the joints in RA. In ax SpA, visfatin seems to be an attractive candidate for radiographic progression, while leptin and adiponectin have negative effects on radiographic progression.

Neutrophil extracellular trap-associated carbamylation and histones trigger osteoclast formation in rheumatoid arthritis

ObjectiveNeutrophil infiltration into the synovial joint is a hallmark of rheumatoid arthritis (RA), a disease characterised by progressive bone erosion. However, the mechanisms by which neutrophils participate in bone destruction...

SMOC2 promotes aggressive behavior of fibroblast-like synoviocytes in rheumatoid arthritis through transcriptional and post-transcriptional regulating MYO1C

Fibroblast-like synoviocytes (FLSs), play a key role in perpetuating synovial inflammation and bone erosion in rheumatoid arthritis (RA), however, the underlying mechanism(s) of RA FLSs activation and aggression remain unclear. Identifying endogenous proteins that selectively target FLSs is urgently needed. Here, we systematically identified that secreted modular calcium-binding protein 2 (SMOC2), was significantly increased in RA FLSs and synovial tissues. SMOC2 knockdown specifically regulated cytoskeleton remodeling and decreased the migration and invasion of RA FLSs. Mechanistically, cytoskeleton-related genes were significantly downregulated in RA FLSs with reduced SMOC2 expression, especially the motor protein myosin1c (MYO1C). SMOC2 controlled MYO1C expression by SRY-related high-mobility group box 4 (SOX4) and AlkB homolog 5 (ALKHB5) mediated-m6A modification through transcriptional and post-transcriptional regulation. Furthermore, intra-articular Ad-shRNA-SMOC2 treatment attenuated synovial inflammation as well as bone and cartilage erosion in rats with collagen-induced arthritis (CIA). Our findings suggest that increased SMOC2 expression in FLSs may contribute to synovial aggression and joint destruction in RA. SMOC2 may serve as a potential target against RA.SMOC2-mediated regulation of the synovial migration and invasion in RA FLSs. In RA FLSs, SMOC2 is significantly increased, leading to the increased level of MYO1C via SOX4-mediated transcriptional regulation and ALKBH5-mediated m6A modification, thereby causing cytoskeleton remodeling and promoting RA FLSs migration and invasion. The Figure was drawn by Figdraw.

Interleukin-13 reduces bone erosion in rheumatoid arthritis by up-regulating osteoprotegerin expression in fibroblast-like synoviocytes : an in vitro and in vivo study.

Bone erosion in rheumatoid arthritis (RA) is partly caused by excessive activation of osteoclasts. Osteoclasts can be derived from RA synovium and their differentiation can be inhibited by osteoprotegerin (OPG), a decoy receptor of the osteoclastogenesis-promoting cytokine receptor activator of nuclear factor κB ligand (RANKL). Fibroblast-like synoviocytes (FLSs) are the main stromal cells in the synovium that can secret OPG. The OPG secretion of FLSs can be modulated by various cytokines. Interleukin (IL)-13 can alleviate bone erosion in RA mouse models, but the mechanisms remain unclear. Therefore, we aimed to investigate whether IL-13 can induce OPG secretion by RA-FLSs, thus ameliorating bone destruction in RA by inhibiting osteoclast differentiation. OPG, RANKL, and IL-13 receptors expression by RA-FLSs were evaluated by RT-qPCR. OPG secretion was determined by ELISA. Western blot was performed to analyse OPG expression and the activation of the STAT6 pathway. IL-13 and (or) OPG siRNA pre-treated RA-FLSs conditioned medium were used in osteoclast induction to test if IL-13 can inhibit osteoclastogenesis by up-regulating OPG in RA-FLSs. Micro-CT and immunofluorescence were performed to determine if IL-13 can induce OPG expression and alleviate bone erosion in vivo. IL-13 can promote OPG expression of RA-FLSs, and the promotion can be overcome by IL-13Rα1 or IL-13Rα2 siRNA transfection, or STAT6 inhibitor. Osteoclast differentiation can be inhibited by IL-13 pre-treated RA-FLSs conditioned medium. The inhibition can be reversed by OPG siRNA transfection. IL-13 injection can increase OPG expression in the joints while reducing bone destruction in collagen-induced arthritis mice. IL-13 can inhibit osteoclastogenesis by up-regulating OPG in RA-FLSs through IL-13 receptors via the STAT6 pathway, thus may ameliorate bone erosion in RA.

IL-1β promotes osteoclastogenesis by increasing the expression of IGF2 and chemokines in non-osteoclastic cells

Bone remodeling mediated by bone-forming osteoblasts (OBs) and bone-resorbing osteoclasts (OCs) maintains bone structure and function. Excessive OC activation leads to bone-destroying diseases such as osteoporosis and bone erosion of rheumatoid arthritis (RA). Differentiation of OCs from bone marrow cells (BMCs) is regulated by the bone microenvironment. The proinflammatory cytokine interleukin (IL)-1β reportedly enhances osteoclastogenesis and plays important roles in RA-associated bone loss. The present study investigated the effect of IL-1β on OC formation via microenvironmental cells. Treating mouse BMCs with IL-1β in the presence of receptor activator of NF-κB ligand and macrophage colony-stimulating factor increased the number of OCs. Real-time RT-PCR revealed increased expression of the IL-1β, IL-1RI, and IL-1RII genes in non-OCs compared with OCs. Removing CD45− cells which cannot differentiate into OCs, from mouse BMCs reduced the IL-1β–mediated enhancement of osteoclastogenesis. IL-1β treatment upregulated the expression of inducible nitric oxide synthase, insulin-like growth factor 2 (IGF2), and the chemokines stromal cell derived factor 1, C-X3-C motif ligand 1 (CX3CL1), and CXCL7 in non-OCs. Neutralizing antibodies against these chemokines and IGF2 suppressed osteoclastogenesis in the presence of IL-1β. These results suggest that IL-1β enhances osteoclastogenesis by upregulating IGF2 and chemokine expression in non-OCs.

Porous Silicon-Based Nanomedicine for Simultaneous Management of Joint Inflammation and Bone Erosion in Rheumatoid Arthritis.

The lack of drugs that target both disease progression and tissue preservation makes it difficult to effectively manage rheumatoid arthritis (RA). Here, we report a porous silicon-based nanomedicine that efficiently delivers an antirheumatic drug to inflamed synovium while degrading into bone-remodeling products. Methotrexate (MTX) is loaded into the porous silicon nanoparticles using a calcium silicate based condenser chemistry. The calcium silicate-porous silicon nanoparticle constructs (pCaSiNPs) degrade and release the drug preferentially in an inflammatory environment. The biodegradation products of the pCaSiNP drug carrier are orthosilicic acid and calcium ions, which exhibit immunomodulatory and antiresorptive effects. In a mouse model of collagen-induced arthritis, systemically administered MTX-loaded pCaSiNPs accumulate in the inflamed joints and ameliorate the progression of RA at both early and established stages of the disease. The disease state readouts show that the combination is more effective than the monotherapies.

Roles of osteoclast-associated receptor in rheumatoid arthritis and osteoarthritis.

Osteoclast-associated receptor (OSCAR) is a member of the leukocyte receptor complex (LRC)-encoded protein family, which is characterized by the presence of immunoglobulin (Ig)-like domains. OSCAR recognizes collagen and was first identified as a co-stimulatory receptor that is needed for complete osteoclast differentiation. However, it is now clear that OSCAR is also expressed by multiple immune cells that participate in many innate and adaptive immune cell activities. We also showed recently that chondrocytes express OSCAR. Our and other studies suggest that OSCAR participates in the pathogenesis of two common joint diseases, namely, rheumatoid arthritis (RA) and osteoarthritis (OA). Specifically, OSCAR promotes osteoclast formation and therefore bone erosion in RA while in OA, it triggers chondrocyte death, thereby inducing cartilage fragility. Significantly, blocking the interaction of OSCAR with its collagen ligand can markedly reduce these activities in vitro and in vivo. Thus, this novel approach may have therapeutic potential for joint diseases.