切换至 "中华医学电子期刊资源库"

中华损伤与修复杂志(电子版) ›› 2016, Vol. 11 ›› Issue (02) : 135 -140. doi: 10.3877/cma.j.issn.1673-9450.2016.02.012

所属专题: 文献

综述

骨转移瘤的溶骨与成骨机制研究进展
雷明星1, 刘耀升1, 刘蜀彬1,()   
  1. 1. 100071 北京,解放军第三〇七医院骨科
  • 收稿日期:2016-02-01 出版日期:2016-04-01
  • 通信作者: 刘蜀彬
  • 基金资助:
    北京市科委首都临床特色课题(z131107002213052)

Research progress on the osteoclastic and osteoblastic mechanisms of bone metastasis

Mingxing Lei1, Yaosheng Liu1, Shubin Liu1,()   

  1. 1. Department of Orthopaedic Surgery, the 307th Hospital of People′s Liberation Army, Beijing 100071, China
  • Received:2016-02-01 Published:2016-04-01
  • Corresponding author: Shubin Liu
  • About author:
    Corresponding author: Liu Shubin, Email:
引用本文:

雷明星, 刘耀升, 刘蜀彬. 骨转移瘤的溶骨与成骨机制研究进展[J]. 中华损伤与修复杂志(电子版), 2016, 11(02): 135-140.

Mingxing Lei, Yaosheng Liu, Shubin Liu. Research progress on the osteoclastic and osteoblastic mechanisms of bone metastasis[J]. Chinese Journal of Injury Repair and Wound Healing(Electronic Edition), 2016, 11(02): 135-140.

骨骼是一种动态重塑的组织,终身以骨质溶解和骨质形成的方式进行骨骼动态重塑循环。骨微环境适宜实体肿瘤定植与生长。实体肿瘤骨转移发生率高,骨转移瘤可以导致明显溶骨性和(或)成骨性骨病灶,如乳腺癌主要以溶骨性病灶为典型,前列腺癌主要以成骨性病灶为主。骨转移瘤的骨骼生理以过度溶骨和(或)成骨为中心。溶骨和成骨的主要机制相互区别独立,本质上均为溶骨与成骨的相关因子打破机体正常骨骼重塑动态循环:RANK-RANKL-OPG系统、甲状旁腺激素相关肽和转移生长因子β参与溶骨,Wnts、内皮素1、甲状旁腺激素相关肽和骨形态发生蛋白参与成骨。骨转移瘤的溶骨与成骨效应都属于正反馈性"恶性循环"。本综述在理解正常骨骼生理与骨骼重塑动态循环的基础上重点阐述骨转移瘤的溶骨和成骨生理机制。探索骨转移瘤的溶骨和成骨生理机制可以为研究者研发靶向药物提供契机。

Bone is a dynamic tissue that undergoes bone remodeling throughout life with the types of osteoblasts and osteoclasts. Bone microenvironments facilitate the colonization and growth of solid tumor. The incidence of bone metastasis from solid tumor is high. Bone metastasis can lead to osteoblastic and/or osteoclastic focuses. Breast cancer is characterized by osteoclastic focuses, while osteoblastic focuses are mainly seen in prostate cancer. The bone physiology of bone metastasis lay center on over osteoclasts and/or osteoblasts. Osteoclastic and osteoblastic mechanisms are varies from each other, Osteoclastic and osteoblastic factors break the normal cycle of bone remodeling in nature. RANK-RANKL-OPG system, parathyroid hormone related protein(PTHrP), and transforming growth factor β are involving in osteoclasts; Wnt, endothelin1, PTHrP, and bone morphogenetic proteins participate in osteoblasts. This review focuses on the mechanisms of osteoclasts and osteoblasts on the basement of understanding the normal bone physiology and cycle of bone remodeling. The exploration of osteoblastic and osteoclastic mechanisms related to bone metastasis can provide opportunities for researcher to prevent and treat tumor metastasis to bone.

表1 骨骼动态重塑相关因子
因子 属性 功能
骨质溶解相关因子 ? ?
? RANKL TNF配体家族成员 RANK的配体,促进破骨细胞前体成熟和成熟破骨细胞骨质溶解
? RANK TNF受体家族成员 RANKL的受体,表达于破骨细胞表面,功能同RANKL
? OPG TNF受体家族成员 RANKL的"饵"受体,阻止RANKL结合RANK,对RANKL的功能起到制约作用
? TRAF6 信号分子 RANK下游信号
? SQSTM1 信号分子 TRAF6下游信号
? NF-κB 转录因子 SQSTM1下游信号,结合破骨细胞分化相关基因
? DC-STAMP 跨膜受体 单核破骨细胞前体融合形成多核破骨细胞所必须
? CCN2 细胞因子 调节RANK-RANKL-OPG系统,增强DC-STAMP表达
? PTHrP 蛋白分子 上调RANKL,下调OPG
? CSF1 细胞因子 促造血干细胞分化为破骨细胞前体和巨噬细胞
? c-src蛋白 信号分子 形成破骨细胞褶皱缘
? TCIRG1/CIC7 基因 编码质子泵和氯泵
? 组蛋白酶K 蛋白水解酶 溶解I型胶原
? RGD序列 多肽分子 介导破骨细胞黏附细胞外基质
骨质形成相关因子 ? ?
? Cbfa1/Osx 转录因子 结合成骨细胞基因增强子
? LRP5 Wnt蛋白受体 作用于Cbfa1/Osx下游,促进成骨
? BMP 生长因子 促进成骨细胞增殖和分化
? Wnt家族蛋白 LRP5配体 Wnt/β-catenin信号途径促进骨质形成
? LRP5 Wnt蛋白受体 传递Wnt蛋白信号
? ET-1 ETAR受体 ET-1/β-catenin信号途径促进骨质形成
? PTHrP 蛋白分子 PTHrP的N-末端片段可以模拟ET-1与成骨细胞ETAR结合促进骨质形成
? PSA 肿瘤特异性抗原 调控RANK-RANKL-OPG系统,灭活PTHrP的溶骨效应
? SOST LRP5"饵"配体 骨细胞产生,拮抗Wnt蛋白效应,抑制骨质形成
? DKK-1 LRP5"饵"配体 拮抗Wnt蛋白效应,抑制骨质形成
图1 骨骼重塑动态循环
图2 骨转移瘤病灶影像学表现
图3 骨转移瘤的溶骨机制
图4 骨转移瘤骨质形成机制
[1]
Freeman AK, Sumathi VP, Jeys L. Metastatic tumours of bone[J]. Surgery (United Kingdom), 2015, 33(1): 34-39.
[2]
Ralston SH. Bone structure and metabolism[J]. Medicine, 2013, 41(10): 581-585.
[3]
Nakashima T, Hayashi M, Fukunaga T, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression[J]. Nat Med, 2011, 17(10): 1231-1234.
[4]
Aoyama E, Kubota S, Khattab HM, et al. CCN2 enhances RANKL-induced osteoclast differentiation via direct binding to RANK and OPG[J]. Bone, 2015, 73: 242-248.
[5]
Nishida T, Emura K, Kubota S, et al. CCN family 2/connective tissue growth factor (CCN2/CTGF) promotes osteoclastogenesis via induction of and interaction with dendritic cell-specific transmembrane protein (DC-STAMP)[J]. J Bone Miner Res, 2011, 26(2): 351-363.
[6]
Nozawa K, Fujishiro M, Kawasaki M, et al. Connective tissue growth factor promotes articular damage by increased osteoclastogenesis in patients with rheumatoid arthritis[J]. Arthritis Res Ther, 2009, 11 (6): R174.
[7]
Ren W, Sun X, Wang K, et al. BMP9 inhibits the bone metastasis of breast cancer cells by downregulating CCN2 (connective tissue growth factor, CTGF) expression[J]. Mol Biol Rep, 2014, 41(3): 1373-1383.
[8]
Wilson SR, Peters C, Saftig P, et al. Cathepsin K activity-dependent regulation of osteoclast actin ring formation and bone resorption[J]. J Biol Chem, 2009, 284(4): 2584-2592.
[9]
Compton JT, Lee FY. A review of osteocyte function and emerging importance of sclerostin[J]. J Bone Joint Surg Am, 2014, 96(19): 1659-1668.
[10]
Nagy V, Penninger JM. The RANKL-RANK Story[J]. Gerontology, 2015, 61(6): 534-542.
[11]
Bussard KM, Gay CV, Mastro AM. The bone microenvironment in metastasis; what is special about bone?[J]. Cancer Metastasis Rev, 2008, 27(1): 41-55.
[12]
Lipton A. Implications of bone metastases and the benefits of bone-targeted therapy[J]. Semin Oncol, 2010, 37(suppl 2): S15-S29.
[13]
Azim HA, Peccatori FA, Brohée S, et al. RANK-ligand (RANKL) expression in young breast cancer patients and during pregnancy[J]. Breast Cancer Res, 2015, 17(1): 24.
[14]
Ibrahim T, Sacanna E, Gaudio M, et al. Role of RANK, RANKL, OPG and CXCR4 tissue markers in predicting bone metastases in breast cancer patients[J]. Clin Breast Cancer, 2011, 11(6): 369-375.
[15]
Sänger N, Ruckhäberle E, Bianchini G, et al. OPG and PgR show similar cohort specific effects as prognostic factors in ER positive breast cancer[J]. Mol Oncol, 2014, 8(7): 1196-1207.
[16]
Clézardin P. The role of RANK/RANKL/osteoprotegerin (OPG) triad in cancer-induced bone diseases: Physiopathology and clinical implications[J]. Bulletin du Cancer, 2011, 98(7): 837-846.
[17]
Roodman GD. Mechanisms of bone metastasis[J]. N Engl J Med, 2004, 350(16): 1655-1664, 1698.
[18]
Wang H, Shen W, Hu X, et al. Quetiapine inhibits osteoclastogenesis and prevents human breast cancer-induced bone loss through suppression of the RANKL-mediated MAPK and NF-κB signaling pathways[J]. Breast Cancer Res Treat, 2015, 149(3): 705-714.
[19]
Sheen YY, Kim MJ, Park SA, et al. Targeting the transforming growth factor-β signaling in cancer therapy[J]. Biomol Ther (Seoul), 2013, 21(5): 323-331.
[20]
VJuárez P, Guise TA. TGF-beta in cancer and bone: implications for treatment of bone metastases[J]. Bone, 2011, 48(1): 23-29.
[21]
Li Y, Drabsch Y, Pujuguet P, et al. Genetic depletion and pharmacological targeting of αv integrin in breast cancer cells impairs metastasis in zebrafish and mouse xenograft models[J]. Breast Cancer Res, 2015, 17: 28.
[22]
Luis-Ravelo D, Antón I, Vicent S, et al. Divergent effects of TGF-β inhibition in bone metastases in breast and lung cancer[J]. Rev Osteoporos Metab Mineral, 2013, 5(2): 79-84.
[23]
Ibaragi S, Shimo T, Iwamoto M, et al. Parathyroid hormone-related peptide regulates matrix metalloproteinase-13 gene expression in bone metastatic breast cancer cells[J]. Anticancer Res, 2010, 30(12): 5029-5036.
[24]
Luco AL, Li J, Ochietti B, et al. Parathyroid hormone-related peptide (PTHrP) blockade inhibits the development of bone metastasis and potentiates the effect of zoledronic acid in vitro and in vivo in a mouse model of breast tumor progression[J]. J Bone Miner Res, 2013, (28 Suppl 1).
[25]
Ibrahim T, Flamini E, Mercatali L, et al. Pathogenesis of osteoblastic bone metastases from prostate cancer[J]. Cancer, 2010, 116(6): 1406-1418.
[26]
Nguyen DX, Chiang AC, Zhang XH, et al. WNT/TCF signaling through LEF1 and HOXB 9 mediates lung adenocarcinoma metastasis[J]. Cell, 2009, 138(1): 51-62.
[27]
Gkotzamanidou M, Dimopoulos MA, Kastritis E, et al. Sclerostin: A possible target for the management of cancer-induced bone disease[J]. Expert Opin Ther Targets, 2012, 16(8): 761-769.
[28]
Rachner TD, Göbel A, Benad-Mehner P, et al. Dickkopf-1 as a mediator and novel target in malignant bone disease[J]. Cancer Lett, 2014, 346(2): 172-177.
[29]
Thudi NK, Martin CK, Murahari S, et al. Dickkopf-1 (DKK-1) stimulated prostate cancer growth and metastases and inhibited bone formation in osteoblastic bone metastases[J]. Prostate, 2011, 71(6): 615-625.
[30]
Todenhöfer T, Leidenberger P, Hennenlotter J, et al. Systemic alterations of Wnt Inhibitors in patients with prostate cancer and bone metastases[J]. Eur Urol, 2014, 13(1): e114.
[31]
D′ Amelio P, Roato I, Oderda M, et al. DKK-1 in prostate cancer diagnosis and follow up[J]. BMC Clin Pathol, 2014, 14(1): 11.
[32]
Zhang H, Yu C, Dai J, et al. Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of β-catenin activation of the DKK1 promoter in prostate cancer[J]. Oncogene, 2014, 33(19): 2464-2477.
[33]
Irani S, Salajegheh A, Smith RA, et al. A review of the profile of endothelin axis in cancer and its management[J]. Crit Rev Oncol Hematol, 2014, 89(2): 314-321.
[34]
Bagnato A, Loizidou M, Pflug BR, et al. Role of the endothelin axis and its antagonists in the treatment of cancer[J]. British J Pharmacol, 2011, 163(2): 220-233.
[35]
Yonou H, Horiguchi Y, Ohno Y, et al. Prostate-specific antigen stimulates osteoprotegerin production and inhibits receptor activator of nuclear factor-kappaB ligand expression by human osteoblasts[J]. Prostate, 2007, 67(8): 840-848.
[36]
Ziaee S, Chung LWK. RANK-and AR-mediated signaling axes in prostate cancer metastasis[J]. Cancer Res, 2015, 75(Suppl 1).
[37]
Kuchimaru T, Kadonosono T, Kondoh SK. Bone resorption facilitates osteoblastic bone metastatic colonization by the functional cooperation between IGF signaling and hypoxia-inducible factor[J]. Mol Imaging Biol, 2015, 17(Suppl 1).
[38]
Jin R, Sterling JA, Edwards JR, et al. Activation of NF-kappa B signaling promotes growth of prostate cancer cells in bone[J]. PLoS One, 2013, 8(4): e60983.
[1] 张晓燕, 肖东琼, 高沪, 陈琳, 唐发娟, 李熙鸿. 转录因子12过表达对脓毒症相关性脑病大鼠大脑皮质的保护作用及其机制[J]. 中华妇幼临床医学杂志(电子版), 2023, 19(05): 540-549.
[2] 邓志平, 张清, 李卓宇, 刘巍峰. 应用计算机导航辅助重建股骨远段恶性肿瘤行骨干节段性切除后缺损的临床观察[J]. 中华损伤与修复杂志(电子版), 2023, 18(05): 381-386.
[3] 陆美琪, 赵洁, 单菲, 王兴蕾, 姜笃银. 药物相关坏疽性脓皮病的研究进展[J]. 中华损伤与修复杂志(电子版), 2023, 18(05): 447-450.
[4] 张潇尹, 于洋. 牙龈卟啉单胞菌介导慢性肾病发生发展的研究进展[J]. 中华口腔医学研究杂志(电子版), 2023, 17(05): 328-334.
[5] 叶晓琳, 刘云飞, 庞明泉, 王海久, 任利, 侯立朝, 于文昊, 王志鑫, 樊海宁. 肝再生细胞来源及调控机制的研究进展[J]. 中华普外科手术学杂志(电子版), 2024, 18(01): 96-99.
[6] 晏晴艳, 雍晓梅, 罗洪, 杜敏. 成都地区老年转移性乳腺癌的预后及生存因素研究[J]. 中华普外科手术学杂志(电子版), 2023, 17(06): 636-638.
[7] 王晓燕, 肖佑, 肖戈, 王真权. 老年结直肠癌肺转移CT特征及高危因素研究[J]. 中华普外科手术学杂志(电子版), 2023, 17(05): 506-509.
[8] 康海, 谭武宾, 周松, 毛正, 米泽振, 李铁求. 膀胱癌根治术后阴茎转移一例报告[J]. 中华腔镜泌尿外科杂志(电子版), 2023, 17(05): 523-525.
[9] 熊风, 林辉煌, 陈晓波. 铥激光在泌尿外科中的临床应用及研究进展[J]. 中华腔镜泌尿外科杂志(电子版), 2023, 17(05): 533-536.
[10] 唐英俊, 李华娟, 王赛妮, 徐旺, 刘峰, 李羲, 郝新宝, 黄华萍. 人脐带间充质干细胞治疗COPD小鼠及机制分析[J]. 中华肺部疾病杂志(电子版), 2023, 16(04): 476-480.
[11] 黄承路, 廖飞, 刘显平, 王志强. 血清外泌体Has_circ_0060937过度表达与NSCLC转移和不良预后的关系[J]. 中华肺部疾病杂志(电子版), 2023, 16(04): 490-494.
[12] 李海明, 刘鸿飞, 李俊. 血清脂蛋白酶水平与COPD患者骨骼肌质量减少的关系[J]. 中华肺部疾病杂志(电子版), 2023, 16(04): 500-503.
[13] 任加发, 邬步云, 邢昌赢, 毛慧娟. 2022年急性肾损伤领域基础与临床研究进展[J]. 中华肾病研究电子杂志, 2023, 12(05): 276-281.
[14] 金刚, 李英真, 施维, 李博. 帕金森病在病理生理学中的研究进展[J]. 中华脑科疾病与康复杂志(电子版), 2023, 13(05): 315-319.
[15] 李田, 徐洪, 刘和亮. 尘肺病的相关研究进展[J]. 中华临床医师杂志(电子版), 2023, 17(08): 900-905.
阅读次数
全文


摘要