Hoogeun Song1,8, Hyunsoo Kim2,8, Kyunghee Lee2, Da-Hye Lee1, Tae-Shin Kim1, Ji Yun Song1, Dongjun Lee1, Dongwook Choi3, Chang-Yong Ko4, Han-Sung Kim4, Hong-In Shin5, Juhyun Choi6, Heedong Park7, Chankyu Park3, Daewon Jeong2 and Dae-Sik Lim1
1.Department of Biological Sciences, National Creative Research Initiatives Center, Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, Daejeon, Korea
2.Department of Microbiology, Aging-Associated Vascular Disease Research Center, Yeungnam University College of Medicine, Daegu, Korea
3.Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
4.Department of Biomedical Engineering, College of Health Science, Institute of Medical Engineering, Yonsei University, Wonju, Korea
5.IHBR, Department of Oral Pathology, School of Dentistry, Kyungpook National University, Daegu, Korea
6.Biosimilar Group, Research and Development Park, LG Life Sciences, Daejeon, Korea
7.Department of Pharmacology, Research and Development Park, LG Life Sciences, Daejeon, Korea
Daewon Jeong, Department of Microbiology, Aging-Associated Vascular Disease Research Center, Yeungnam University College of Medicine, Daegu 705-717, Korea.
Dae-Sik Lim, Department of Biological Sciences, National Creative Research Initiatives Center, Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
8These authors contributed equally to this work
RASSF2 belongs to the Ras-association domain family (RASSF) of proteins, which may be involved in the Hippo signalling pathway. However, the role of RASSF2 in vivo is unknown. Here, we show that Rassf2 knockout mice manifest a multisystemic phenotype including haematopoietic anomalies and defects in bone remodelling. Bone marrow (BM) transplantation showed that Rassf2 -/- BM cells had a normal haematopoietic reconstitution activity, indicating no intrinsic haematopoietic defects. Notably, in vitro differentiation studies revealed that ablation of Rassf2 suppressed osteoblastogenesis but promoted osteoclastogenesis. Co-culture experiments showed that an intrinsic defect in osteoblast differentiation from Rassf2-/- osteoblast precursors likely leads to both haematopoiesis and osteoclast defects in Rassf2 -/- mice. Moreover, Rassf2 deficiency resulted in hyperactivation of nuclear factor (NF)-κB during both osteoclast and osteoblast differentiation. RASSF2 associated with IκB kinase (IKK) α and β forms, and suppressed IKK activity. Introduction of either RASSF2 or a dominant-negative form of IKK into Rassf2 -/- osteoclast or osteoblast precursors inhibited NF-κB hyperactivation and normalized osteoclast and osteoblast differentiation. These observations indicate that RASSF2 regulates osteoblast and osteoclast differentiation by inhibiting NF-κB signalling.
Keywords:bone remodelling; Hippo pathway; osteoblastogenesis; osteoclastogenesis; RASSF2