Long noncoding RNA hottip maintained skeletal homeostasis via suppressing the enhancer of zeste homolog 2 (Ezh2)/histone methylation regulatory axis

Objective

Recent evidence underscores the pivotal role of long noncoding RNAs (lncRNAs) in orchestrating bone remodeling and skeletal homeostasis by harmonizing osteoblast and osteoclast development. Notably, the oncogenic lncRNA, Hottip, implicated in osteogenesis regulation, remains insufficiently elucidated. This study aims to delineate Hottip's role in bone remodeling and skeletal homeostasis.

Methods

Hottip knockout mice were generated to discern its impact on bone metabolism. In vitro experiments probed cellular mechanisms influenced by Hottip, while molecular interactions were explored to understand its basis. The therapeutic potential of Hottip overexpression was investigated through in vivo experiments.

Results

Hottip knockout mice displayed disrupted bone metabolism, aberrant tissue, and compromised quality, leading to delayed fracture healing. In vitro, Hottip knockdown impeded osteoblast differentiation, while promoting osteoclast differentiation, with converse effects upon Hottip overexpression. Mechanistically, Hottip physically interacted with EZH2, inducing its degradation and enhancing osteogenic gene transcription by suppressing H3K9me3 and H3K27me3. In vivo experiments validated Hottip overexpression's potential to promote bone regeneration and hasten fracture healing.

Conclusion

In summary, this study identifies Hottip as a critical regulator in osteoblast and osteoclast differentiation, crucial for maintaining skeletal homeostasis. Hottip emerges as a promising therapeutic target for enhancing bone regeneration. These findings contribute valuable insights into lncRNA-mediated mechanisms governing skeletal dynamics.