Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK.
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
Bone. 2020 Aug;137:115455. doi: 10.1016/j.bone.2020.115455. Epub 2020 May 28.
Bone morphogenetic proteins (BMPs) are multifunctional secreted cytokines that act in a highly context-dependent manner. BMP action extends beyond the induction of cartilage and bone formation, to encompass pivotal roles in controlling tissue and organ homeostasis during development and adulthood. BMPs signal via plasma membrane type I and type II serine/threonine kinase receptors and intracellular SMAD transcriptional effectors. Exquisite temporospatial control of BMP/SMAD signalling and crosstalk with other cellular cues is achieved by a series of positive and negative regulators at each step in the BMP/SMAD pathway. The interaction of BMP ligand with its receptors is carefully controlled by a diverse set of secreted antagonists that bind BMPs and block their interaction with their cognate BMP receptors. Perturbations in this BMP/BMP antagonist balance are implicated in a range of developmental disorders and diseases, including cancer. Here, we provide an overview of the structure and function of secreted BMP antagonists, and summarize recent novel insights into their role in cancer progression and bone metastasis. Gremlin1 (GREM1) is a highly studied BMP antagonist, and we will focus on this molecule in particular and its role in cancer. The therapeutic potential of pharmacological inhibitors for secreted BMP antagonists for cancer and other human diseases will also be discussed.
骨形态发生蛋白（BMPs）是多功能分泌细胞因子，以高度依赖上下文的方式发挥作用。BMP 的作用不仅局限于诱导软骨和骨形成，还包括在发育和成年期控制组织和器官稳态方面的关键作用。BMP 通过质膜 I 型和 II 型丝氨酸/苏氨酸激酶受体和细胞内 SMAD 转录效应物发挥作用。通过 BMP/SMAD 途径中每个步骤的一系列正调节剂和负调节剂，实现了对 BMP/SMAD 信号的精细时空控制和与其他细胞信号的串扰。BMP 配体与其受体的相互作用受到一系列不同的分泌拮抗剂的严格控制，这些拮抗剂结合 BMP 并阻止其与同源 BMP 受体相互作用。这种 BMP/BMP 拮抗剂平衡的破坏与一系列发育障碍和疾病有关，包括癌症。在这里，我们概述了分泌型 BMP 拮抗剂的结构和功能，并总结了它们在癌症进展和骨转移中的作用的最新新见解。Gremlin1（GREM1）是一种研究较多的 BMP 拮抗剂，我们将特别关注该分子及其在癌症中的作用。还将讨论针对分泌型 BMP 拮抗剂的药理学抑制剂在癌症和其他人类疾病中的治疗潜力。
