The Transcriptional Repressor LRF Regulates Osteoclastogenesis

Objectives: Understanding the transcriptional regulation of osteoclasts is important for the development of new therapeutic strategies for dental diseases. Methods: To elucidate the physiological role of leukemia/lymphoma-related factor (LRF), a transcriptional repressor known to be expressed in osteoclasts, during osteoclastogenesis, we generated two types of stage-specific conditional knockout mice of LRF (LRF^{Flox/Flox Mx1 cre+} and LRF^ΔOc/ΔOc) by crossing LRF-flox mice with Mx1-Cre transgenic and Ctsk-Cre knock-in mice, respectively. LRF^{Flox/Flox Mx1 cre+} mice, in which the LRF gene is deleted in osteoclast precursors, exhibited a low bone mass due to the increased number of osteoclasts. Results: In vitro osteoclastogenesis of LRF^{Flox/Flox Mx1 cre+} cells was markedly enhanced through the upregulation in nuclear factor of activated T cells c1 expression. In contrast, LRF^ΔOc/ΔOc mice, in which the LRF gene is deleted at a later stage of osteoclast differentaition, exhibited a high bone mass due to the decreased activity of osteoclasts. Conclusions: LRF plays a biphasic role in the regulation of osteoclastogenesis, depending on the differentiation stage. This study was supported by the GCOE program and the ERATO project.