Yang Xue D, Haga Christopher L, Phinney Donald G
Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL33458, USA.
Curr Drug Targets. 2025;26(5):350-366. doi: 10.2174/0113894501359782241216082049.
Diseases affecting bone encompass a spectrum of disorders, from prevalent conditions such as osteoporosis and Paget's disease, collectively impacting millions, to rare genetic disorders including Fibrodysplasia Ossificans Progressiva (FOP). While several classes of drugs, such as bisphosphonates, synthetic hormones, and antibodies, are utilized in the treatment of bone diseases, their efficacy is often curtailed by issues of tolerability and high incidence of adverse effects. Developing therapeutic agents for bone diseases is hampered by the fact that numerous pathways regulating bone metabolism also perform pivotal functions in other organ systems. Consequently, the selection of an appropriate target is a complicated process despite the significant demand for novel medications to address bone diseases. Research has shown the role of various cell signaling pathways, including Wnt, PTHR1, CASR, BMPRs, OSCAR, and TWIST1, in the regulation of osteogenesis, bone remodeling, and homeostasis. Disruptions in bone homeostasis can result in decreased bone density and the onset of osteoporosis. There remains a need for the development of drugs that can enhance bone remodeling with improved side effects profiles. The exploration of promising targets to stimulate bone formation has the potential to significantly advance the field of bone-related medical care, thereby improving the quality of life for millions. Additionally, a deeper understanding of anabolic and catabolic pathway mechanisms could enable future studies to explore synergistic effects between unrelated pathways. Herein, we explore potential drug targets that may be exploited therapeutically using small molecule agonists or antagonists to promote bone remodeling and discuss their advantages and limitations.
影响骨骼的疾病涵盖了一系列病症，从骨质疏松症和佩吉特病等常见疾病（这些疾病共同影响着数百万人）到罕见的遗传性疾病，如进行性骨化性纤维发育不良（FOP）。虽然几类药物，如双膦酸盐、合成激素和抗体，被用于治疗骨骼疾病，但其疗效往往受到耐受性问题和高不良反应发生率的限制。由于调节骨代谢的众多途径在其他器官系统中也发挥着关键作用，因此开发治疗骨骼疾病的药物受到阻碍。因此，尽管对治疗骨骼疾病的新型药物有巨大需求，但选择合适的靶点是一个复杂的过程。研究表明，各种细胞信号通路，包括Wnt、PTHR1、CASR、BMPR、OSCAR和TWIST1，在骨生成、骨重塑和体内平衡的调节中发挥作用。骨稳态的破坏会导致骨密度降低和骨质疏松症的发生。仍然需要开发能够改善副作用谱的同时增强骨重塑的药物。探索有前景的刺激骨形成的靶点有可能显著推动骨相关医疗领域的发展，从而改善数百万人的生活质量。此外，对合成代谢和分解代谢途径机制的更深入理解可以使未来的研究探索不相关途径之间的协同作用。在此，我们探索可能通过小分子激动剂或拮抗剂进行治疗性利用以促进骨重塑的潜在药物靶点，并讨论它们的优缺点。
