Osteoporosis associated with rheumatoid arthritis

Patients with rheumatoid arthritis(RA) develop both generalized and periarticular osteoporosis. Both of them are believed to be associated with increased production of inflammatory cytokines(TNF alpha, IL-1 beta, IL-6) and increased formation and activation of osteoclasts. Whether glucocorticoids work positively or negatively on generalized/periarticular osteoporosis is still controversial. RANKL has been shown to be expressed on T cells and fibroblast-like cells in the synovium, thus 'RANKL-RANK' pathway is likely to play an important role in periarticular osteoporosis and bone erosion as well as generalized osteoporosis. Among various therapies for generalized/periarticular osteoporosis in RA, anti-cytokine antibodies/antagonists and osteoclast inhibitors including bisphosphonates are promising.     

RANKL-RANK信号传导与类风湿关节炎骨破坏相关性研究

目的：探讨RANKL-RANK信号传导系统与类风湿关节炎（RA）患者炎性关节骨破坏的相关性。方法：应用ELISA方法检测OPG、RANKL、抗CCP抗体、RF-IgA、RF-IgG、RF-IgM在RA患者外周血的表达;应用单克隆抗体,通过免疫组织化学方法检测RA活动期、缓解期及健康对照关节滑膜组织中RANKL, OPG的表达及分布状况。结果：显示OPG、RANKL、抗CCP、RF-IgA、RF-IgG、RF-IgM抗体在RA患者外周血的表达：早期RA组和非早期RA组指标均显著高于正常对照组（P〈0.01）,OPG、RANKL的表达在早期RA组高于非早期RA组（P〈0.05）;各组滑膜组织中OPG、RANKL的表达,骨侵蚀组与非骨侵蚀组检测数值均显著高于正常对照组（P〈0.01）;且骨侵蚀组与非骨侵蚀组检测数值比较,OPG、RANKL均具有显著性差别（P〈0.05）。结论： RANKL-RANK/OPG系统在RA关节骨侵蚀发病早期既已表达,且随着病情的活动变化而变化。     

The Death Receptor 3-TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints that is associated with cartilage and bone destruction. Death Receptor 3 (DR3), a tumor necrosis factor (TNF) receptor superfamily member, has recently been associated with the pathogenesis of RA. We demonstrate that absence of DR3 confers resistance to the development of adverse bone pathology in experimental antigen-induced arthritis (AIA). DR3^ko mice exhibited a reduction in all histopathological hallmarks of AIA but, in particular, failed to develop subchondral bone erosions and were completely protected from this characteristic of AIA. In contrast, TNF-like protein 1A (TL1A), the ligand for DR3, exacerbated disease in a dose- and DR3-dependent fashion. Analysis of osteoclast number within AIA joint revealed a reduction in areas susceptible to bone erosion in DR3^ko mice, whereas in vitro osteoclastogenesis assays showed that TL1A could directly promote osteoclastogenesis in mouse and man. Treatment with antagonistic anti-TL1A mAb protected animals in a systemic model of RA disease collagen-induced arthritis. We therefore conclude that the DR3–TL1A pathway regulates joint destruction in two murine models of arthritis and represents a potential novel target for therapeutic intervention in inflammatory joint disease.     

Regulation of osteoclastogenesis by activated T cells

Bone destruction in rheumatoid arthritis (RA) is caused by osteoclasts, multinuclear cells of the monocyte/macrophage lineage. Since osteoclast differentiation factor RANKL (receptor activator of NF-kappaB ligand) is expressed on activated T cells and T cells, especially Th1 type cells, are implicated in the pathogenesis of RA, it has been believed that they play an important role in the osteoclastogenesis in RA lesions. However, main Th1-type cytokine IFN-gamma strongly suppresses osteoclastogenesis, casting doubt on the relevancy of Th1 cells as stimulators of osteoclastogenesis. Recently, IL-17 from T cells has been reported to enhance osteoclastogenesis. Characterizing real Th subsets which support osteoclastogenesis would be beneficial to solving a clinically important problem, bone destruction in RA.     

Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis

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

Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin

Autoimmunity is complicated by bone loss. In human rheumatoid arthritis (RA), the most severe inflammatory joint disease, autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. We therefore hypothesized that these autoantibodies directly influence bone metabolism. Here, we found a strong and specific association between autoantibodies against citrullinated proteins and serum markers for osteoclast-mediated bone resorption in RA patients. Moreover, human osteoclasts expressed enzymes eliciting protein citrullination, and specific N-terminal citrullination of vimentin was induced during osteoclast differentiation. Affinity-purified human autoantibodies against mutated citrullinated vimentin (MCV) not only bound to osteoclast surfaces, but also led to robust induction of osteoclastogenesis and bone-resorptive activity. Adoptive transfer of purified human MCV autoantibodies into mice induced osteopenia and increased osteoclastogenesis. This effect was based on the inducible release of TNF-α from osteoclast precursors and the subsequent increase of osteoclast precursor cell numbers with enhanced expression of activation and growth factor receptors. Our data thus suggest that autoantibody formation in response to citrullinated vimentin directly induces bone loss, providing a link between the adaptive immune system and bone.     

Mechanism of the bone destruction in rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by the presence of inflammatory synovitis accompanied by cartilage and bone destruction. Histological examination of RA pannus shows a number of osteoclasts on the surface of the destructed bone. RA synovial tissues produce a variety of proinflammatory cytokines and growth factors that may increase osteoclast formation, activity, and/or survival. Synovial fibroblasts from RA patients express high levels of RANKL, which is essential for the differentiation of osteoclasts, and therefore, RANKL can be a good therapeutic target of joint destruction in RA.     

Intravenously delivered glucocorticoid liposomes inhibit osteoclast activity and bone erosion in murine antigen-induced arthritis

The objective of this study was to determine the effect of systemic delivery of prednisolone phosphate (PLP) encapsulated within long circulating ‘stealth’ liposomes on bone erosion and osteoclast activity during experimental antigen-induced arthritis (AIA). Liposomal PLP strongly suppressed knee joint swelling, synovial infiltrate and bone erosion in antigen-induced arthritis. The number of active osteoclasts was not only suppressed in bone lesions near inflamed synovium, but also within the trabecular bone of the tibia, suggesting a systemic suppression of osteoclast activation. Furthermore, liposomal PLP directly blocked osteoclast differentiation and bone resorption in vitro while it also suppressed expression of osteoclast differentiation factors M-CSF and RANKL in the synovium. Targeting studies showed that liposomes are most efficiently phagocytosed by macrophages and early precursors of osteoclasts in the bone marrow rather than by mature osteoclasts, indicating a possible inhibition of osteoclast differentiation from an early stage. Conclusion: Liposomal glucocorticoid delivery rather than free PLP offers a more efficacious way to inhibit both inflammation and bone erosion in rheumatoid arthritis.     

NF-κB p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism

TNF and RANKL mediate bone destruction in common bone diseases, including osteoarthritis and RA. They activate NF-κB canonical signaling directly in osteoclast precursors (OCPs) to induce osteoclast formation in vitro. However, unlike RANKL, TNF does not activate the alternative NF-κB pathway efficiently to process the IκB protein NF-κB p100 to NF-κB p52, nor does it appear to induce osteoclast formation in vivo in the absence of RANKL. Here, we show that TNF limits RANKL- and TNF-induced osteoclast formation in vitro and in vivo by increasing NF-κB p100 protein accumulation in OCPs. In contrast, TNF induced robust osteoclast formation in vivo in mice lacking RANKL or RANK when the mice also lacked NF-κB p100, and TNF-Tg mice lacking NF-κB p100 had more severe joint erosion and inflammation than did TNF-Tg littermates. TNF, but not RANKL, increased OCP expression of TNF receptor–associated factor 3 (TRAF3), an adapter protein that regulates NF-κB p100 levels in B cells. TRAF3 siRNA prevented TNF-induced NF-κB p100 accumulation and inhibition of osteoclastogenesis. These findings suggest that upregulation of TRAF3 or NF-κB p100 expression or inhibition of NF-κB p100 degradation in OCPs could limit bone destruction and inflammation-induced bone loss in common bone diseases.     

Diagnosis and prediction of joint destruction found in patients with rheumatoid arthritis using by biochemical markers

Rheumatoid arthritis(RA) is characterized by localized destruction of synovium, cartilage, and bone. Loss of bone in RA is not only localized in joints but is also generalized. In RA, bone loss seems to be related to elevated bone resorption, while data of bone formation are conflicting. Increased bone absorption markers are associated with bone erosion at baseline and may predict radiographic progression. Treatment with TNF blockers and/or disease-modifying anti-rheumatic drug therapy cause the reduction of levels of bone resorption markers. MMP-3 is involved in the pathogenesis of RA, since the synovial fluid from RA patients contains a large amount of MMP-3. The serum concentration of MMP-3 is a useful marker for predicting bone damage in the early stage of RA, and the suppression of MMP -3 production may be an effective therapeutic approach for patients with early RA.     

IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion

Bone destruction is the most difficult target in the treatment of rheumatoid arthritis (RA). Here, we report that local overexpression of IL-4, introduced by a recombinant human type 5 adenovirus vector (Ad5E1mIL-4) prevents joint damage and bone erosion in the knees of mice with collagen arthritis (CIA). No difference was noted in the course of CIA in the injected knee joints between Ad5E1mIL-4 and the control vector, but radiographic analysis revealed impressive reduction of joint erosion and more compact bone structure in the Ad5E1mIL-4 group. Although severe inflammation persisted in treated mice, Ad5E1mIL-4 prevented bone erosion and diminished tartrate-resistant acid phosphatase (TRAP) activity, indicating that local IL-4 inhibits the formation of osteoclast-like cells. Messenger RNA levels of IL-17, IL-12, and cathepsin K in the synovial tissue were suppressed, as were IL-6 and IL-12 protein production. Osteoprotegerin ligand (OPGL) expression was markedly suppressed by local IL-4, but no loss of OPG expression was noted with Ad5E1mIL-4 treatment. Finally, in in vitro studies, bone samples of patients with arthritis revealed consistent suppression by IL-4 of type I collagen breakdown. IL-4 also enhanced synthesis of type I procollagen, suggesting that it promoted tissue repair. These findings may have significant implications for the prevention of bone erosion in arthritis.     

早期类风湿性关节炎手腕部的MRI影像观察

目的评估MRI对手腕部早期类风湿性关节炎的诊断价值.方法对30例临床诊断为早期类风湿性关节炎的患者进行手腕部X线平片和MRI检查,比较2种技术对病变的显示能力.结果 X线平片显示所有患者均未见骨侵蚀, 17例可见关节肿胀,28例可见骨质疏松,10例关节间隙轻度狭窄.MRI显示20例关节面骨侵蚀,所有30例均可见关节滑膜增厚、关节积液以及关节周围炎性渗出,23例可见血管翳形成,7例合并关节周围肌腱韧带损伤.平片和MRI对病变关节数目的检出率分别为20%及81%.结论 MRI是诊断早期类风湿性关节炎的较好方法.     

NF-(kappa)B-inducing kinase controls lymphocyte and osteoclast activities in inflammatory arthritis

NF-(kappa)B is an important component of both autoimmunity and bone destruction in RA. NF-(kappa)B-inducing kinase (NIK) is a key mediator of the alternative arm of the NF-(kappa)B pathway, which is characterized by the nuclear translocation of RelB/p52 complexes. Mice lacking functional NIK have no peripheral lymph nodes, defective B and T cells, and impaired receptor activator of NF-kappaB ligand-stimulated osteoclastogenesis. We investigated the role of NIK in murine models of inflammatory arthritis using Nik-/- mice. The serum transfer arthritis model is initiated by preformed antibodies and required only intact neutrophil and complement systems in recipients. While Nik-/- mice had inflammation equivalent to that of Nik+/+ controls, they showed significantly less periarticular osteoclastogenesis and less bone erosion. In contrast, Nik-/- mice were completely resistant to antigen-induced arthritis (AIA), which requires intact antigen presentation and lymphocyte function but not lymph nodes. Additionally, transfer of Nik+/+ splenocytes or T cells to Rag2-/- mice conferred susceptibility to AIA, while transfer of Nik-/- cells did not. Nik-/- mice were also resistant to a genetic, spontaneous form of arthritis, generated in mice expressing both the KRN T cell receptor and H-2. Thus, NIK is important in the immune and bone-destructive components of inflammatory arthritis and represents a possible therapeutic target for these diseases.     

Synovium as a source of increased amino-terminal parathyroid hormone-related protein expression in rheumatoid arthritis. A possible role for locally produced parathyroid hormone-related protein in the pathogenesis of rheumatoid arthritis.

Proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin 1 (IL-1), mediate the joint destruction that characterizes rheumatoid arthritis (RA). Previous studies have shown that parathyroid hormone-related protein (PTHrP) is a member of the cascade of proinflammatory cytokines induced in parenchymal organs during lethal endotoxemia. To test the hypothesis that NH2-terminal PTHrP, a potent bone resorbing agent, could also be a member of the synovial cascade of tissue-destructive cytokines whose expression is induced in RA, PTHrP expression was examined in synovium and synoviocytes obtained from patients with RA and osteoarthritis (OA). PTHrP production, as determined by measurement of immunoreactive PTHrP(1-86) in tissue explant supernatants, was increased 10-fold in RA versus OA synovial tissue. Synovial lining cells and fibroblast-like cells within the pannus expressed both PTHrP and the PTH/PTHrP receptor, findings that were confirmed by in vitro studies of cultured synoviocytes. TNF-alpha and IL-1beta stimulated PTHrP expression in synoviocytes, while dexamethasone and interferon-gamma, agents with some therapeutic efficacy in the treatment of RA, inhibited PTHrP release. Treatment of synoviocytes with PTHrP(1-34) stimulated IL-6 secretion. These results suggest that proinflammatory cytokine-stimulated production of NH2-terminal PTHrP by synovial tissue directly invading cartilage and bone in RA may mediate joint destruction through direct effects on cartilage or bone, or, indirectly, via the induction of mediators of bone resorption in the tumor-like synovium.     

IL-1β–driven osteoclastogenic Tregs accelerate bone erosion in arthritis

IL-1β is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1β contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn^–/–), we observed that IL-1β blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4⁺Foxp3⁺ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn^–/– Tregs and wild-type Tregs differentiated with IL-1β accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKL^hiFoxp3⁺ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1β–induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.     

Prospects of treatment using interferon for bone diseases

Osteoblasts and osteoclasts produce a variety of cytokines to maintain bone homeostasis. One of the most important cytokines, receptor activator of nuclear factor-IkappaB ligand (RANKL), is essential for osteoclastogenesis. Recently, it was shown that activated T cells promote osteoclastogenesis through RANKL expression and also negatively affect osteoclastogenesis through interferon (IFN)-gamma production. Additionally, it was revealed that IFN-beta was involved in osteoclast regulation by signaling cross-talk with RANKL and that it contributed to the maintenance of normal bone mass. These studies indicate that there are complex regulatory interactions between bone-remodeling cells and immune cells, which depend on the balance between RANKL and IFN. Thus, the interaction between T cells and bone cells could be physiologically critical for the maintenance of normal bone metabolism, and IFN might be an attractive cytokine for use in therapy for bone disease in pathological bone resorptive conditions such as rheumatoid arthritis, osteoporosis, osteomyelitis and bone metastasis of cancers.     

Growth hormone, VEGF and FGF: involvement in rheumatoid arthritis

Adult rheumatoid arthritis (RA), a systemic autoimmune disorder of unknown etiology, is characterized by dysfunctional cellular and humoral immunity, enhanced migration and attachment of peripheral macrophages and pro-inflammatory leukocytes to the synovium and articular cartilage of diarthrodial joints. The progressive destruction of cartilage and bone in RA is a result of elevated pro-inflammatory cytokine gene expression, synovial neovascularization, proteinase-mediated dissolution of articular cartilage matrix and osteoclast-mediated subchondral bone resorption. Juvenile chronic arthritis (JCA) is disease with manifestations similar to adult RA that occurs in childhood. JCA usually causes precocious joint destruction and often also presents with evidence of growth plate anomalies and reduced stature. Three proteins play an integral role in both adult RA and JCA. These are somatotropin (also called pituitary growth hormone (GH)), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). GH is responsible for regulating long bone growth and skeletal maturation through its capacity to stimulate insulin-like growth factor-I (IGF-1) synthesis by hepatocytes. Mechanisms responsible for growth plate disturbances and short stature in children with JCA include deficient GH production, GH-insensitivity resulting from defects in the GH receptor, suppressed IGF-1 synthesis or neutralization of IGF-1 action by IGF-1 binding proteins (IGFBPs). In addition, GH has also been implicated in perpetuating inflammation and pain in adult RA. VEGF has been shown to be the critical angiogenesis factor responsible for vascular proliferation and blood vessel invasion of the synovial lining membrane in RA. Acidic FGF (FGF-1) and basic FGF (FGF-2) have also been implicated in aberrant synoviocyte proliferation (i.e. synovial hyperplasia) and apoptosis resistance in adult RA.     

类风湿关节炎患者自身抗体及关节损伤因子检出的临床意义

目的:检测类风湿关节炎(rheumatoid arthritis,RA)患者关节损伤因子及多种自身抗体,探讨其与RA发病间的关联性。方法:采用酶联免疫吸附试验(ELISA)法检测15例RA患者血清和滑膜液中关节损伤相关因子基质金属蛋白酶3(matrix metalloproteinases 3,MMP3)和基质金属蛋白酶组织抑制因子1(tissue inhibitor of metalloproteinase 1,TIMP-1)、骨破坏因子——核因子κB受体活化因子配基(receptor activator of NF-κB ligand,RANKL)和其保护性抑制剂骨保护素(osteoprotegerin,OPG)的表达。检测6例RA患者的sIL-6和sIL-6Rα、sgp130表达水平,同时设骨关节炎(osteoarthritis,OA)为对照组(6例)及正常对照组(8例)。分析22例RA患者临床常用的检测指标,包括类风湿因子、抗环瓜氨酸多肽抗体、葡萄糖-6-磷酸异构酶及23例RA患者抗胶原Ⅱ抗体的表达,并以OA患者为对照;针对用合成的EBV肽段和人HLA-DR4肽段检测和分析15例RA患者抗EBV肽段和抗HLA-DR4肽段抗体的阳性率。结果:RA患者关节腔滑膜液中MMP3和TIMP1表达异常,滑膜液MMP3/TIMP1比值显著高于相应的血清相应比值(P<0.001)。与OA组相比,RA患者血清及滑膜液中RANKL水平升高(P<0.05)。RA患者体内IL-6信号系统表达异常,其滑膜液中sIL-6Rα水平高于OA组(P<0.05),而天然拮抗剂sgp130的血清水平则显著低于OA组血清中(P