骨质疏松症的相关信号通路及其药物研究进展
Research Progress of Related Signal Pathway and Drugs in Osteoporosis
摘要: 骨质疏松症(Osteoporosis, OP)是一种常见的老年性骨病,由于骨的形成和吸收之间的平衡被破坏导致损伤骨的微观结构,最终骨脆性增加从而造成骨折风险上升和骨折率增加。骨骼的吸收与形成与骨骼代谢的动态和平衡息息相关,可通过不同的方式来影响骨骼代谢的动态和平衡进而影响骨骼重建。在其涉及的机制中,骨代谢和信号通路是紧密相连的,它们都对骨质疏松症做出了重要贡献。为了进一步治疗骨质疏松症,在本文中探究了与骨代谢有关的信号通路的研究,重点是OPG/RANKL/RANK、Wnt/β-catenin和组蛋白酶K信号通路,以及相关的靶点和抗骨质疏松症药物。
Abstract: Osteoporosis (OP) is a common bone disease of old age, due to the disruption of the balance between bone formation and resorption leading to damage to the microstructure of the bone, and ultimately an increase in bone brittleness resulting in an increased risk of fracture and an increased fracture rate. Bone resorption and formation are closely related to the dynamics and balance of bone metabolism, which can be influenced in different ways to affect bone reconstruction. Among the mechanisms involved, bone metabolism and signaling pathways are closely linked, and both of them make important contributions to osteoporosis. To further the treatment of osteoporosis, the study of signaling pathways related to bone metabolism is explored in this paper, focusing on the OPG/RANKL/RANK, Wnt/β-catenin and histone enzyme K signaling pathways, as well as related targets and anti-osteoporosis drugs.
文章引用:胡晟, 梁杰. 骨质疏松症的相关信号通路及其药物研究进展[J]. 临床医学进展, 2024, 14(3): 1853-1858. https://doi.org/10.12677/acm.2024.143916

参考文献

[1] 屈泽超, 王栋, 冯铭哲, 等. 破骨细胞分化信号传导及相关天然化合物的研究进展[J]. 中国骨质疏松杂志, 2023, 29(2): 282-287 296.
[2] 中华医学会骨科学分会. 骨质疏松性骨折诊疗指南(2022年版) [J]. 中华骨科杂志, 2022, 42(22): 1473-1491.
[3] 中华医学会骨质疏松和骨矿盐疾病分会. 原发性骨质疏松症诊疗指南(2017) [J]. 中华骨质疏松和骨矿盐疾病杂志, 2017, 10(5): 413-443.
[4] Chang, X., Xu, S. and Zhang, H. (2022) Regulation of Bone Health through Physical Exercise: Mechanisms and Types. Frontiers in Endocrinology (Lausanne), 13, Article ID: 1029475. [Google Scholar] [CrossRef] [PubMed]
[5] 《中国骨质疏松杂志》社, 《中国骨质疏松杂志》骨代谢专家组. 骨质疏松分子生物学研究专家共识[J/OL]. 中国骨质疏松杂志.
https://link.cnki.net/urlid/11.3701.r.20231201.1403.002, 2023-12-01.
[6] Li, S.S., He, S.H., Xie, P.Y., et al. (2021) Recent Progresses in the Treatment of Osteoporosis. Frontiers in Pharmacology, 12, Article No. 16. [Google Scholar] [CrossRef] [PubMed]
[7] Galeone, A., Grano, M. and Brunetti, G. (2023) Tumor Necrosis Factor Family Members and Myocardial Ischemia-Reperfusion Injury: State of the Art and Therapeutic Implications. International Journal of Molecular Sciences, 24, Article No. 4606. [Google Scholar] [CrossRef] [PubMed]
[8] Udagawa, N., Koide, M., Nakamura, M., et al. (2021) Osteoclast Differentiation by RANKL and OPG Signaling Pathways. Journal of Bone and Mineral Metabolism, 39, 19-26. [Google Scholar] [CrossRef] [PubMed]
[9] Takegahara, N., Kim, H. and Choi, Y. (2022) RANKL Biology. Bone, 159, Article ID: 116353. [Google Scholar] [CrossRef] [PubMed]
[10] Cannata-Andia, J.B., Carrillo-Lopez, N., Messina, O.D., et al. (2021) Pathophysiology of Vascular Calcification and Bone Loss: Linked Disorders of Ageing? Nutrients, 13, Article No. 3835. [Google Scholar] [CrossRef] [PubMed]
[11] Zhang, L., Zeng, F., Jiang, M., et al. (2022) Roles of Osteoprotegerin in Endocrine and Metabolic Disorders through Receptor Activator of Nuclear Factor Kappa-B Ligand/Receptor Activator of Nuclear Factor Kappa-B Signaling. Frontiers in Cell and Developmental Biology, 10, Article ID: 1005681. [Google Scholar] [CrossRef] [PubMed]
[12] 赵常红, 李世昌, 李沛鸿, 等. 调节破骨细胞功能的相关信号分子的研究进展[J]. 中国骨质疏松杂志, 2021, 27(9): 1361-1365.
[13] 陈浩然, 于冬冬, 齐鹏坤, 等. 基于OPG/RANKL/RANK信号通路治疗绝经后骨质疏松症中西医研究进展[J]. 辽宁中医药大学学报, 2022, 24(7): 179-183.
[14] 金健, 金大地. 利塞膦酸钠抑制大鼠骨髓内脂肪细胞分化及脂肪细胞核因子κB受体活化因子配体蛋白的表达[J]. 南方医科大学学报, 2019, 39(8): 987-992.
[15] 钟亚春, 陆璇, 徐立. 利塞膦酸钠和阿仑膦酸钠治疗对股骨粗隆下侧皮质骨密度变化的影响对比研究[J]. 中国骨质疏松杂志, 2019, 25(6): 842-846.
[16] Compston, J.E., Mcclung, M.R. and Leslie, W.D. (2019) Osteoporosis. The Lancet, 393, 364-376. [Google Scholar] [CrossRef
[17] Anastasilakis, A.D., Makras, P., Yavropoulou, M.P., et al. (2021) Denosumab Discontinuation and the Rebound Phenomenon: A Narrative Review. Journal of Clinical Medicine, 10, Article No. 152. [Google Scholar] [CrossRef] [PubMed]
[18] Anastasilakis, A.D., Papapoulos, S.E., Polyzos, S.A., et al. (2019) Zoledronate for the Prevention of Bone Loss in Women Discontinuing Denosumab Treatment. A Prospective 2-Year Clinical Trial. Journal of Bone and Mineral Research, 34, 2220-2228. [Google Scholar] [CrossRef] [PubMed]
[19] Nakai, Y., Okamoto, K., Terashima, A., et al. (2019) Efficacy of an Orally Active Small-Molecule Inhibitor of RANKL in Bone Metastasis. Bone Research, 7, Article No. 1. [Google Scholar] [CrossRef] [PubMed]
[20] Liang, B., Burley, G., Lin, S., et al. (2022) Osteoporosis Pathogenesis and Treatment: Existing and Emerging Avenues. Cellular & Molecular Biology Letters, 27, Article No. 72. [Google Scholar] [CrossRef] [PubMed]
[21] 陈桐莹. 基于Wnt/β-Catenin信号通路研究肉苁蓉苷A调控成骨细胞自噬的机制[D]: [硕士学位论文]. 广州: 广州中医药大学, 2021.
[22] 郭一览, 孙朋. Wnt/β-Catenin信号通路在运动调控骨形成中的机制[J]. 生命科学, 2022, 34(12): 1519-1529.
[23] 丁小芬, 周友龙, 田明月, 等. Wnt/β-Catenin信号通路与膝关节骨性关节炎软骨代谢[J]. 中国老年学杂志, 2022, 42(23): 5917-5921.
[24] 万冰莹, 陈岱. 慢性肾脏病矿物质及骨代谢紊乱的研究进展[J]. 实用中医内科杂志, 2022, 36(8): 68-75.
[25] 褚赞波, 邹荣鑫, 黄海燕, 等. 破骨细胞功能调控与骨吸收抑制剂[J]. 中华骨质疏松和骨矿盐疾病杂志, 2018, 11(5): 509-514.
[26] 陈文文, 孙雯雯, 尹玲, 等. 新型骨硬化蛋白抑制剂Romosozumab在骨质疏松症治疗中的应用: 从临床试验到临床应用[J]. 中国医院药学杂志, 2021, 41(1): 115-118.
[27] Mcclung, M.R., Grauer, A., Boonen, S., et al. (2014) Romosozumab in Postmenopausal Women with Low Bone Mineral Density. The New England Journal of Medicine, 370, 412-420. [Google Scholar] [CrossRef
[28] Fixen, C. and Tunoa, J. (2021) Romosozumab: A Review of Efficacy, Safety, and Cardiovascular Risk. Current Osteoporosis Reports, 19, 15-22. [Google Scholar] [CrossRef] [PubMed]
[29] Recknor, C.P., Recker, R.R., Benson, C.T., et al. (2015) The Effect of Discontinuing Treatment with Blosozumab: Follow-Up Results of a Phase 2 Randomized Clinical Trial in Postmenopausal Women with Low Bone Mineral Density. Journal of Bone and Mineral Research, 30, 1717-1725. [Google Scholar] [CrossRef] [PubMed]
[30] Van Dinther, M., Zhang, J., Weidauer, S.E., et al. (2013) Anti-Sclerostin Antibody Inhibits Internalization of Sclerostin and Sclerostin-Mediated Antagonism of Wnt/LRP6 Signaling. PLOS ONE, 8, E62295. [Google Scholar] [CrossRef] [PubMed]
[31] Boschert, V., Van Dinther, M., Weidauer, S., et al. (2013) Mutational Analysis of Sclerostin Shows Importance of the Flexible Loop and the Cystine-Knot for Wnt-Signaling Inhibition. PLOS ONE, 8, E81710. [Google Scholar] [CrossRef] [PubMed]
[32] Mijanovic, O., Jakovleva, A., Brankovic, A., et al. (2022) Cathepsin K in Pathological Conditions and New Therapeutic and Diagnostic Perspectives. International Journal of Molecular Sciences, 23, Article No. 13762. [Google Scholar] [CrossRef] [PubMed]
[33] Mukherjee, K. and Chattopadhyay, N. (2016) Pharmacological Inhibition of Cathepsin K: A Promising Novel Approach for Postmenopausal Osteoporosis Therapy. Biochemical Pharmacology, 117, 10-19. [Google Scholar] [CrossRef] [PubMed]
[34] Lotinun, S., Kiviranta, R., Matsubara, T., et al. (2013) Osteoclast-Specific Cathepsin K Deletion Stimulates S1P-Dependent Bone Formation. Journal of Clinical Investigation, 123, 666-681. [Google Scholar] [CrossRef
[35] Stone, J.A., Mccrea, J.B., Witter, R., et al. (2019) Clinical and Translational Pharmacology of the Cathepsin K Inhibitor Odanacatib Studied for Osteoporosis. British Journal of Clinical Pharmacology, 85, 1072-1083. [Google Scholar] [CrossRef] [PubMed]
[36] Jensen, P.R., Andersen, T.L., Pennypacker, B.L., et al. (2014) The Bone Resorption Inhibitors Odanacatib and Alendronate Affect Post-Osteoclastic Events Differently in Ovariectomized Rabbits. Calcified Tissue International, 94, 212-222. [Google Scholar] [CrossRef] [PubMed]
[37] Bone, H.G., Mcclung, M.R., Roux, C., et al. (2010) Odanacatib, a Cathepsin-K Inhibitor for Osteoporosis: A Two-Year Study in Postmenopausal Women with Low Bone Density. Journal of Bone and Mineral Research, 25, 937-947. [Google Scholar] [CrossRef] [PubMed]
[38] Chapurlat, R.D. (2015) Odanacatib: A Review of Its Potential in the Management of Osteoporosis in Postmenopausal Women. Therapeutic Advances in Musculoskeletal Disease, 7, 103-109. [Google Scholar] [CrossRef
[39] Jerome, C., Missbach, M. and Gamse, R. (2012) Balicatib, a Cathepsin K Inhibitor, Stimulates Periosteal Bone Formation in Monkeys. Osteoporosis International, 23, 339-349. [Google Scholar] [CrossRef] [PubMed]
[40] Runger, T.M., Adami, S., Benhamou, C.L., et al. (2012) Morphea-Like Skin Reactions in Patients Treated with the Cathepsin K Inhibitor Balicatib. Journal of the American Academy of Dermatology, 66, E89-E96. [Google Scholar] [CrossRef] [PubMed]