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

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 that is associated with HBM. Subsequent analysis in 1,465 Chinese subjects revealed that heterozygous individuals had higher bone density compared with subjects with WT Mutant increased the formation of the CD31Emcn endothelium in the bone marrow, which stimulated angiogenesis during osteogenesis. Mechanistically, mutant directly binds to Krüppel-like factor 3 (KLF3) to inhibit its activity. Mice depleted of in endothelial cells showed a high abundance of CD31Emcn 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 CD31Emcn vessels and bone formation. Our findings revealed a specific mutation in lncRNA that is involved in the pathogenesis of HBM and provides a new target to treat osteoporosis.