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

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 <i>Reg1cp</i> that is associated with HBM. Subsequent analysis in 1,465 Chinese subjects revealed that heterozygous <i>Reg1cp</i> individuals had higher bone density compared with subjects with WT <i>Reg1cp</i> Mutant <i>Reg1cp</i> increased the formation of the CD31^hiEmcn^hi endothelium in the bone marrow, which stimulated angiogenesis during osteogenesis. Mechanistically, mutant <i>Reg1cp</i> directly binds to Krüppel-like factor 3 (KLF3) to inhibit its activity. Mice depleted of <i>Klf3</i> 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 <i>Reg1cp</i> that is involved in the pathogenesis of HBM and provides a new target to treat osteoporosis.