Effect of MIP-1 delta on Osteoclast Development and Pathological Bone Resorption

MIP-1 delta 对破骨细胞发育和病理性骨吸收的影响

• 批准号: 7922524
• 负责人: Scott L Kominsky
• 金额: $ 24.35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922524
• 关键词: Affect; Area; Biological; Bone Development; Bone Marrow; Bone Resorption; Bone Surface; Bone neoplasms; Bone remodeling; Cell Line; Cells; Chemicals; Chemotaxis; Clinical; Clinical Research; Collagen; Comprehension; Coupled; Critical Pathways; Cyclophosphamide; Data; Development; Disease; EMSA; Equilibrium; Event; FOS gene; Family; Family member; Future; Human; Image; Immunofluorescence Immunologic; In Vitro; Injection of therapeutic agent; Institutes; Knowledge; Macrophage Inflammatory Protein-1; Macrophage Inflammatory Proteins; Malignant Neoplasms; Measurement; Mediating; Medical; Medicine; Metastatic Neoplasm to the Bone; Morbidity - disease rate; Neoplasm Metastasis; Nude Mice; Operative Surgical Procedures; Orthopedics; Osteoblasts; Osteoclasts; Osteogenesis; Osteolytic; Osteoporosis; Pain; Pathological fracture; Pathway interactions; Patient Care; Patients; Periodontitis; Play; Prevention; Prevention therapy; Process; Production; Protein Family; Public Health; Quality of life; Relative (related person); Renal Cell Carcinoma; Reporting; Rheumatoid Arthritis; Role; Serum; Signal Pathway; Signal Transduction; Skeleton; TNFSF11 gene; TRANCE protein; Testing; Therapeutic; Thick; Tissue Microarray; Tissues; Work; base; bone; bone fatigue; bone loss; bone strength; chemokine; cost; crosslink; design; improved; in vivo; inhibitor/antagonist; insight; joint destruction; member; mouse model; novel; phase 3 study; pre-clinical; prevent; prognostic indicator; public health relevance; response; skeletal disorder; substantia spongiosa; tartrate-resistant acid phosphatase; therapeutic target; tibia

DESCRIPTION (provided by applicant): Bone remodeling is a continuously occurring balance of bone destruction followed by bone formation, which maintains bone strength by replacing damaged bone with new bone. Unfortunately, diseases affecting the skeleton such as osteoporosis, rheumatoid arthritis, and cancer, tilt the delicate balance of bone destruction and bone formation toward the prior, leading to excessive bone loss. In many cases, this bone loss causes significant morbidity including severe pain, joint destruction, and pathological fracture. Despite advances in our comprehension of the bone remodeling process, the mechanisms responsible for pathological bone loss initiated by skeletal diseases such as osteoporosis, rheumatoid arthritis, and cancer remain poorly understood. Improved understanding of these mechanisms is vital to the development of more effective therapeutics. Recent evidence suggests that members of the chemokine family of chemical messengers may play a role in mediating pathological bone loss. The chemokine macrophage inflammatory protein (MIP)-3a, whose expression has been reported in both rheumatoid arthritis and periodontitis, has been shown to enhance the development of bone-destroying cells called osteoclasts (OCL). Interestingly, we recently found levels of the MIP family member MIP-1d to be significantly elevated in renal cell carcinoma bone metastasis (RBM), which frequently causes excessive bone destruction. Interestingly, MIP-1d has also been detected in synovial tissue from rheumatoid arthritis patients. Subsequent preliminary studies in vitro demonstrated that MIP-1d not only stimulates recruitment of immature OCL, but also enhances differentiation into mature OCL. Based on these preliminary data, we hypothesize that MIP-1d plays a direct role in mediating pathological bone loss by enhancing stimulation of key signaling pathways of OCL formation in combination with RANKL. In preliminary studies we found that both RANKL and MIP-1d were capable of stimulating NF-?B and PLC?2 signaling, two critical pathways for OCL formation, while other important pathways in OCL formation were unaffected by MIP-1d. We will initially investigate our hypothesis by determining the ability of MIP-1d to enhance NF-?B and PLC?2 activation in combination with RANKL. Subsequently, we will utilize chemical inhibitors of NF-?B and PLC?2 to examine the functional role of each pathway in MIP-1d-enhanced OCL formation in vitro. Lastly, using human RBM cell lines in which MIP-1d production has been increased or silenced, we will examine the effect of MIP-1d on bone destruction in vivo using a mouse model of RBM- induced bone loss. In addition, we will determine the clinical correlation between MIP-1d expression in primary RCC and the subsequent development of osteolytic metastasis. These studies will further our knowledge regarding the role of chemokines in pathological bone loss and may provide a novel target for prevention and therapy, thus having the potential to greatly impact the future of Orthopaedic medicine. PUBLIC HEALTH RELEVANCE: This work may identify MIP-1d as a therapeutic target for the prevention and treatment of pathological bone loss, provide insight into how the effects of MIP-1d may be abrogated, and determine the potential utility of MIP-1d as a prognostic indicator for both the development of osteolytic metastasis and the therapeutic response to anti- RANKL therapy, which is currently in phase 3 studies evaluating its effects in patients with conditions resulting in bone loss (eg. osteoporosis, rheumatoid arthritis, bone metastasis, etc.). Therefore, this work is timely and has the potential to influence both clinical prevention and treatment decisions, providing the framework necessary for future pre-clinical and clinical studies, and will greatly advance our current understanding of the biological mechanisms involved in the development of pathological bone loss in diseases such as rheumatoid arthritis and cancer, which affect millions of people each year. If more effective medical therapy can be instituted prior to or early in the course of disease, the development of severe bone destruction may be prevented or delayed, resulting in improved quality of life and decreased costs of care for these patients who often require surgical treatment, thus greatly impacting public health.

描述（由申请人提供）：骨重建是骨破坏与骨形成之间的持续平衡，通过用新骨替换受损骨来维持骨强度。不幸的是，影响骨骼的疾病，如骨质疏松症，类风湿性关节炎和癌症，使骨破坏和骨形成的微妙平衡向前倾斜，导致过度的骨丢失。在许多情况下，这种骨丢失会导致严重的发病率，包括剧烈疼痛、关节破坏和病理性骨折。尽管我们对骨重建过程的理解有所进步，但对骨质疏松症、类风湿性关节炎和癌症等骨骼疾病引起的病理性骨丢失的机制仍知之甚少。更好地理解这些机制对于开发更有效的治疗方法至关重要。 最近的证据表明，化学信使趋化因子家族的成员可能在介导病理性骨丢失中发挥作用。据报道，趋化因子巨噬细胞炎症蛋白（MIP）-3a在类风湿性关节炎和牙周炎中表达，已被证明可以增强称为破骨细胞（OCL）的骨破坏细胞的发育。有趣的是，我们最近发现MIP家族成员MIP-1d的水平在肾细胞癌骨转移（RBM）中显著升高，这通常会导致过度的骨破坏。有趣的是，MIP-1d也在类风湿性关节炎患者的滑膜组织中检测到。随后的体外初步研究表明，MIP-1d不仅刺激未成熟OCL的募集，而且还促进向成熟OCL的分化。基于这些初步数据，我们假设MIP-1d通过增强OCL形成的关键信号通路的刺激与RANKL结合，在介导病理性骨丢失中发挥直接作用。 在初步研究中，我们发现RANKL和MIP-1d都能够刺激NF-？B和PLC？MIP-1d对OCL形成的两条关键通路-2信号通路的影响不明显，而对OCL形成的其他重要通路的影响不明显。我们将首先调查我们的假设，通过确定MIP-1d的能力，以提高NF-？B和PLC？2激活与RANKL的组合。随后，我们将利用NF-？B和PLC？2检测MIP-1d促进OCL形成中各通路的功能作用。最后，使用MIP-1d产生增加或沉默的人RBM细胞系，我们将使用RBM诱导的骨丢失的小鼠模型检查MIP-1d对体内骨破坏的作用。此外，我们将确定原发性RCC中MIP-1d表达与随后溶骨性转移发展之间的临床相关性。这些研究将进一步了解趋化因子在病理性骨丢失中的作用，并可能为预防和治疗提供新的靶点，从而有可能极大地影响骨科医学的未来。 公共卫生相关性：这项工作可以确定MIP-1d作为预防和治疗病理性骨丢失的治疗靶点，提供MIP-1d的作用如何被消除的见解，并确定MIP-1d作为溶骨性转移发展和抗RANKL治疗反应的预后指标的潜在效用，其目前处于3期研究中，评估其在导致骨丢失的患者中的作用（例如，骨质疏松症、类风湿性关节炎、骨转移等）。因此，这项工作是及时的，有可能影响临床预防和治疗决策，为未来的临床前和临床研究提供必要的框架，并将大大推进我们目前对疾病（如类风湿性关节炎和癌症）中病理性骨丢失发展的生物学机制的理解，这些疾病每年影响数百万人。如果能在发病前或发病早期采取更有效的药物治疗，就可以预防或延缓严重骨质破坏的发展，从而提高这些经常需要手术治疗的患者的生活质量，降低其护理成本，从而极大地影响公共卫生。

项目成果

MIP-1δ activates NFATc1 and enhances osteoclastogenesis: involvement of both PLCγ2 and NFκB signaling.

MIP-1δ 激活 NFATc1 并增强破骨细胞生成：PLCγ2 和 NFκB 信号传导的参与。

• DOI: 10.1371/journal.pone.0040799
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Weber,KristyL;Doucet,Michele;Shaner,Adam;Hsu,Nigel;Huang,David;Fogel,Jenna;Kominsky,ScottL
• 通讯作者: Kominsky,ScottL