Inhibition of osteoblast function in bone erosion in rheumatoid arthritis

类风湿性关节炎骨侵蚀中成骨细胞功能的抑制

• 批准号: 8493996
• 负责人: Ellen M Gravallese
• 金额: $ 30.08万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8493996
• 关键词: Address; Affect; Animal Model; Antibodies; Antigens; Applications Grants; Arthritis; Attention; Attenuated; BMP2 gene; BMP3 gene; Biological Assay; Bone Resorption; Cells; Chronic; Chronic Disease; Data; Defect; Disease; Equilibrium; Excision; Family; Fibroblasts; Glycogen Synthase Kinase 3; Grant; Histologic; Human; Immunohistochemistry; In Situ Hybridization; In Vitro; Inflammation; Inflammatory; Joint by Site; Joints; Laboratories; Lesion; Link; MAPK8 gene; Measurement; Mediating; Mediator of activation protein; Modeling; Modification; Monitor; Morbidity - disease rate; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Outcome; Pathogenesis; Pathway interactions; Patients; Pilot Projects; Play; Process; RNA; Regulation; Research Design; Rheumatoid Arthritis; Role; Serum; Signal Pathway; Signal Transduction; Site; Source; Synovial Membrane; TNF gene; TNFSF11 gene; Testing; Three-dimensional analysis; Up-Regulation; Western Blotting; base; bone; bone loss; bone morphogenic protein; cell type; chronic autoimmune disease; cytokine; design; disability; improved; in vitro Assay; in vivo; inhibitor/antagonist; intervention effect; novel; osteoblast differentiation; osteoclastogenesis; osteogenic; protein expression; public health relevance; research study

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a debilitating chronic disease that leads to focal loss of bone in inflamed joints. Osteoclast-mediated resorption is one mechanism for loss of articular bone. However, data from our laboratory demonstrate a defect in the maturation of bone-forming osteoblasts (OBs) at sites of articular bone loss (erosions), with an accompanying inhibition in the formation of mineralized bone at sites of inflammation. OB differentiation and function is dependant upon positive signaling through the Bone Morphogenic Protein (BMP) and Wingless-type (Wnt) signaling pathways. We have identified expression of inhibitors of OB differentiation and function at sites of bone erosion in the murine serum transfer arthritis (STA) model. Expression of BMP3, an inhibitor of pro-osteogenic BMP2 signaling, and of two Wnt signaling pathway inhibitors, Dickkopf1 (DKK1) and secreted Frizzled related-protein1 (sFRP1), is induced at sites of erosion, implicating these factors in the inhibition of OB maturation and function in RA. In this grant we will evaluate the contribution of two intersecting pathways by testing the hypothesis that inflammation in RA synovium leads to modifications in the BMP and Wnt signaling pathways that inhibit OB function, and thereby accelerates focal articular bone loss. In Aim 1, we will test the hypothesis that BMP3 plays a unique role in the inhibition of OB function at sites of erosion, and acts through modulation of Wnt signaling. The process of bone erosion will be evaluated in BMP3 deficient and control littermate mice with STA by histologic quantitation, quantitation of articular bone by microCT, and dynamic histomorphometry. The regulation of Wnt signaling by BMP3 will be determined in focused SuperArray assays in vitro. Aim 2 will test the hypothesis that enhanced Wnt signaling is protective in focal bone erosion in RA due to augmentation of OB-mediated bone formation. This will be achieved by promoting Wnt signaling in two animal models of arthritis by inhibiting GSK-3 (Part A) or by specifically blocking DKK1 activity (Part B). TNFa, a critical cytokine in RA pathogenesis, is an inhibitor of OB differentiation and function in vitro, and induces DKK1 in synovial fibroblasts. In Aim 3, the effects of TNFa on expression of BMP3 and Wnt antagonists in cell types found within arthritic lesions will be determined in vitro, and potential interactions between the BMP and Wnt signaling pathways in these cell types will also be determined. Cellular sources of these factors will be identified in animal models in vivo. These studies are designed to identify novel targets for the augmentation of bone formation in RA.

描述(申请人提供)：类风湿性关节炎(RA)是一种使人衰弱的慢性疾病，导致发炎关节的局部骨质丢失。破骨细胞介导的骨吸收是关节骨丢失的一种机制。然而，我们实验室的数据显示，关节骨丢失(侵蚀)部位的成骨细胞(OBS)成熟缺陷，伴随而来的是炎症部位矿化骨形成的抑制。OB的分化和功能依赖于通过骨形态发生蛋白(BMP)和无翼型(WNT)信号通路的阳性信号。在小鼠血清转移性关节炎(STA)模型中，我们已经确定了成骨细胞分化和功能抑制因子在骨侵蚀部位的表达。促成骨BMP2信号通路的抑制因子BMP3和两种Wnt信号通路抑制因子Dickkopf1(Dkk1)和分泌型FrizzledRelated-Protein 1(SFRP1)在侵蚀部位被诱导表达，提示这些因素在抑制类风湿关节炎OB的成熟和功能中起作用。在这项捐赠中，我们将通过测试假设来评估两条交叉通路的贡献，即RA滑膜中的炎症导致BMP和WNT信号通路的修改，从而抑制OB功能，从而加速局灶性关节骨丢失。在目标1中，我们将验证BMP3在抑制侵蚀部位的OB功能方面发挥独特作用，并通过调节Wnt信号发挥作用的假说。通过组织学定量、关节骨显微CT定量和动态组织形态计量学方法评价BMP3缺陷和对照仔鼠STA的骨侵蚀过程。BMP3对Wnt信号的调节作用将在体外的聚焦超阵列实验中确定。目的2将验证这一假设，即增强的Wnt信号在由于增强OB介导的骨形成而导致的RA局灶性骨侵蚀中具有保护作用。这将通过在两种关节炎动物模型中通过抑制GSK-3(A部分)或通过特定地阻断Dkk1活性(B部分)来促进Wnt信号传递来实现。TnFa是RA发病机制中的关键细胞因子，在体外是OB分化和功能的抑制因子，并诱导滑膜成纤维细胞中的Dkk1。在目标3中，将在体外确定TNFa对关节炎病变内发现的不同类型细胞中BMP3和Wnt拮抗剂表达的影响，并将确定这些细胞中BMP和Wnt信号通路之间的潜在相互作用。这些因子的细胞来源将在活体动物模型中确定。这些研究旨在确定RA骨形成增强的新靶点。

项目成果

Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment.

• DOI: 10.1038/nrrheum.2012.153
• 发表时间: 2012-11
• 期刊: Nature reviews. Rheumatology

IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis.

• DOI: 10.1186/s13075-016-0998-x
• 发表时间: 2016-05-10
• 期刊: Arthritis research & therapy
• 影响因子: 4.9
• 作者: Shaw AT;Maeda Y;Gravallese EM
• 通讯作者: Gravallese EM

Impact of inflammation on the osteoblast in rheumatic diseases.

• DOI: 10.1007/s11914-013-0183-y
• 发表时间: 2014-03
• 期刊: CURRENT OSTEOPOROSIS REPORTS
• 影响因子: 4.3
• 作者: Baum, Rebecca;Gravallese, Ellen M.
• 通讯作者: Gravallese, Ellen M.

Mediators of inflammation and bone remodeling in rheumatic disease.

• DOI: 10.1016/j.semcdb.2015.10.013
• 发表时间: 2016-01
• 期刊: Seminars in cell & developmental biology
• 影响因子: 7.3
• 作者: Shaw AT;Gravallese EM
• 通讯作者: Gravallese EM

RANK-Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis.

• DOI: 10.1002/art.39837
• 发表时间: 2016-12
• 期刊: ARTHRITIS & RHEUMATOLOGY
• 影响因子: 13.3
• 作者: O'Brien, William;Fissel, Brian M.;Maeda, Yukiko;Yan, Jing;Ge, Xianpeng;Gravallese, Ellen M.;Aliprantis, Antonios O.;Charles, Julia F.
• 通讯作者: Charles, Julia F.