Krüppel-like factor 3 inhibition by mutated lncRNA Reg1cp results in human high bone mass syndrome

Mi Yang; Qi Guo; Hui Peng; Yu-Zhong Xiao; Ye Xiao; Yan Huang; Chang-Jun Li; Tian Su; Yun-Lin Zhang; Min-Xiang Lei; Hui-Ling Chen; Tie-Jian Jiang; Xiang-Hang Luo

doi:10.1084/jem.20181554

Krüppel-like factor 3 inhibition by mutated lncRNA Reg1cp results in human high bone mass syndrome

J Exp Med. 2019 Aug 5;216(8):1944-1964. doi: 10.1084/jem.20181554. Epub 2019 Jun 13.

Authors

Mi Yang^#¹, Qi Guo^#^{1

2}, Hui Peng^#¹, Yu-Zhong Xiao^{1

2}, Ye Xiao¹, Yan Huang¹, Chang-Jun Li¹, Tian Su¹, Yun-Lin Zhang³, Min-Xiang Lei¹, Hui-Ling Chen¹, Tie-Jian Jiang¹, Xiang-Hang Luo⁴

Affiliations

¹ Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China.
² Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China.
³ Department of Metabolic Endocrinology, The Second People's Hospital of Xiangxiang, Xiangxiang, China.
⁴ Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China xianghangluo@hotmail.com.

^# Contributed equally.

Abstract

High bone mass (HBM) is usually caused by gene mutations, and its mechanism remains unclear. In the present study, we identified a novel mutation in the long noncoding RNA Reg1cp that is associated with HBM. Subsequent analysis in 1,465 Chinese subjects revealed that heterozygous Reg1cp individuals had higher bone density compared with subjects with WT Reg1cp Mutant Reg1cp increased the formation of the CD31^hiEmcn^hi endothelium in the bone marrow, which stimulated angiogenesis during osteogenesis. Mechanistically, mutant Reg1cp directly binds to Krüppel-like factor 3 (KLF3) to inhibit its activity. Mice depleted of Klf3 in endothelial cells showed a high abundance of CD31^hiEmcn^hi vessels and increased bone mass. Notably, we identified a natural compound, Ophiopogonin D, which functions as a KLF3 inhibitor. Administration of Ophiopogonin D increased the abundance of CD31^hiEmcn^hi vessels and bone formation. Our findings revealed a specific mutation in lncRNA Reg1cp that is involved in the pathogenesis of HBM and provides a new target to treat osteoporosis.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Animals
Bone Density / genetics
China
Cohort Studies
Endothelial Progenitor Cells / metabolism
Female
Heterozygote
Humans
Hyperostosis, Cortical, Congenital / blood
Hyperostosis, Cortical, Congenital / genetics*
Hyperostosis, Cortical, Congenital / metabolism*
Hyperostosis, Cortical, Congenital / pathology
Kruppel-Like Transcription Factors / antagonists & inhibitors*
Kruppel-Like Transcription Factors / genetics
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Mutation*
Neovascularization, Physiologic / genetics
Osteogenesis / drug effects
Osteogenesis / genetics
Osteopetrosis / blood
Osteopetrosis / genetics*
Osteopetrosis / metabolism*
Osteopetrosis / pathology
Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
RNA, Long Noncoding / genetics*
RNA, Long Noncoding / metabolism*
Saponins / administration & dosage
Saponins / pharmacology
Sialoglycoproteins / metabolism
Spirostans / administration & dosage
Spirostans / pharmacology
Young Adult

Substances

EMCN protein, human
Emcn protein, mouse
KLF3 protein, human
Klf3 protein, mouse
Kruppel-Like Transcription Factors
PECAM1 protein, human
Pecam1 protein, mouse
Platelet Endothelial Cell Adhesion Molecule-1
RNA, Long Noncoding
Saponins
Sialoglycoproteins
Spirostans
ophiopogonin D

Supplementary concepts

Worth syndrome