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EMBO J., publication 6 January 2012; doi:10.1038/emboj.2011.480 Ablation of Rassf2 induces bone defects and subsequent haematopoietic anomalies in mice

Abstract

Hoogeun Song^1,8, Hyunsoo Kim^2,8, 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

Correspondence to:
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

논문정보

형식Research article
게재일2012년 01월 (BRIC 등록일 )
연구진국내 연구진
분야 생명과학 > 발생생물학

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