Division of Biomedical Sciences, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama, 350-1241, Japan; Project of Clinical and Basic Research for FOP, Saitama Medical University, Saitama, Japan.
Division of Biomedical Sciences, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama, 350-1241, Japan.
Bone. 2020 Aug;137:115410. doi: 10.1016/j.bone.2020.115410. Epub 2020 May 11.
Bone morphogenetic protein (BMP) signaling regulates the physiological and pathological development of skeletal tissues. Activin receptor-like kinase 2 (ALK2) is a BMP type I transmembrane serine/threonine kinase receptor. Recently, a p.K400E mutation was found in ALK2 in a patient with diffuse idiopathic skeletal hyperostosis (DISH), which is a disorder characterized by calcification and ossification of spinal ligaments and entheses. We report here the functional characterization of ALK2 p.K400E in vitro. Cells overexpressing ALK2 p.K400E activated BMP signaling in response to osteogenic BMP ligands. However, ALK2 p.K400E was not activated by a nonosteogenic ligand, Activin A. BMP signaling through ALK2 p.K400E was further enhanced by the coexpression of a BMP type II receptor. The type II receptor increased the phosphorylation level of ALK2 p.K400E, suggesting that ALK2 p.K400E is a hypersensitive mutant to the BMP type II receptor kinases. Our findings suggest that pathological calcification and ossification in DISH are caused by overactivated BMP signaling through ALK2 p.K400E enhanced by type II receptors in response to osteogenic BMPs rather than Activin A.
骨形态发生蛋白（BMP）信号调节骨骼组织的生理和病理发育。激活素受体样激酶 2（ALK2）是 BMP 型 I 跨膜丝氨酸/苏氨酸激酶受体。最近，在弥漫特发性骨肥厚症（DISH）患者的 ALK2 中发现了一个 p.K400E 突变，DISH 是一种以脊柱韧带和附著处的钙化和骨化为特征的疾病。我们在此报告了体外 ALK2 p.K400E 的功能特征。过表达 ALK2 p.K400E 的细胞对成骨 BMP 配体激活 BMP 信号。然而，ALK2 p.K400E 不会被非成骨配体激活素 A 激活。ALK2 p.K400E 通过 BMP 型 II 受体的共表达进一步增强了 BMP 信号。该 II 型受体增加了 ALK2 p.K400E 的磷酸化水平，表明 ALK2 p.K400E 是对 BMP 型 II 受体激酶的超敏突变体。我们的发现表明，DISH 中的病理性钙化和骨化是由 ALK2 p.K400E 通过 II 型受体增强的过激活 BMP 信号引起的，这种增强是对成骨 BMP 而不是激活素 A 的反应。
