Ablation of Rassf2 induces bone defects and subsequent haematopoietic anomalies in mice

Hoogeun Song, Hyunsoo Kim, Kyunghee Lee, Da Hye Lee, Tae Shin Kim, Ji Yun Song, Dongjun Lee, Dongwook Choi, Chang Yong Ko, Hansung Kim, Hong In Shin, Juhyun Choi, Heedong Park, Chankyu Park, Daewon Jeong, Dae Sik Lim

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1147-1159
Number of pages13
JournalEMBO Journal
Volume31
Issue number5
DOIs
Publication statusPublished - 2012 Mar 7

Fingerprint

Osteoblasts
Ablation
Osteoclasts
Bone
Bone and Bones
Defects
Bone Remodeling
Hematopoiesis
Coculture Techniques
Bone Marrow Transplantation
Cell culture
Osteogenesis
Knockout Mice
Bone Marrow Cells
Phosphotransferases
Phenotype
Proteins
Experiments

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Song, H., Kim, H., Lee, K., Lee, D. H., Kim, T. S., Song, J. Y., ... Lim, D. S. (2012). Ablation of Rassf2 induces bone defects and subsequent haematopoietic anomalies in mice. EMBO Journal, 31(5), 1147-1159. https://doi.org/10.1038/emboj.2011.480
Song, Hoogeun ; Kim, Hyunsoo ; Lee, Kyunghee ; Lee, Da Hye ; Kim, Tae Shin ; Song, Ji Yun ; Lee, Dongjun ; Choi, Dongwook ; Ko, Chang Yong ; Kim, Hansung ; Shin, Hong In ; Choi, Juhyun ; Park, Heedong ; Park, Chankyu ; Jeong, Daewon ; Lim, Dae Sik. / Ablation of Rassf2 induces bone defects and subsequent haematopoietic anomalies in mice. In: EMBO Journal. 2012 ; Vol. 31, No. 5. pp. 1147-1159.
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abstract = "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.",
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Song, H, Kim, H, Lee, K, Lee, DH, Kim, TS, Song, JY, Lee, D, Choi, D, Ko, CY, Kim, H, Shin, HI, Choi, J, Park, H, Park, C, Jeong, D & Lim, DS 2012, 'Ablation of Rassf2 induces bone defects and subsequent haematopoietic anomalies in mice', EMBO Journal, vol. 31, no. 5, pp. 1147-1159. https://doi.org/10.1038/emboj.2011.480

Ablation of Rassf2 induces bone defects and subsequent haematopoietic anomalies in mice. / Song, Hoogeun; Kim, Hyunsoo; Lee, Kyunghee; Lee, Da Hye; Kim, Tae Shin; Song, Ji Yun; Lee, Dongjun; Choi, Dongwook; Ko, Chang Yong; Kim, Hansung; Shin, Hong In; Choi, Juhyun; Park, Heedong; Park, Chankyu; Jeong, Daewon; Lim, Dae Sik.

In: EMBO Journal, Vol. 31, No. 5, 07.03.2012, p. 1147-1159.

Research output: Contribution to journalArticle

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T1 - Ablation of Rassf2 induces bone defects and subsequent haematopoietic anomalies in mice

AU - Song, Hoogeun

AU - Kim, Hyunsoo

AU - Lee, Kyunghee

AU - Lee, Da Hye

AU - Kim, Tae Shin

AU - Song, Ji Yun

AU - Lee, Dongjun

AU - Choi, Dongwook

AU - Ko, Chang Yong

AU - Kim, Hansung

AU - Shin, Hong In

AU - Choi, Juhyun

AU - Park, Heedong

AU - Park, Chankyu

AU - Jeong, Daewon

AU - Lim, Dae Sik

PY - 2012/3/7

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N2 - 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.

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