Volume 14 Supplement 1

Proceedings of the 8th Global Arthritis Research Network (GARN) Meeting and 1st Bio-Rheumatology International Congress (BRIC)

Open Access

A systems approach reveals that the musculoskeletal tissues development and homeostasis network

  • Hiroshi Asahara1, 2, 3, 4
Arthritis Research & Therapy201214(Suppl 1):O28

DOI: 10.1186/ar3583

Published: 29 February 2012

Materials and methods

We created a whole-mount in situ hybridization database, termed EMBRYS http://embrys.jp/embrys/html/MainMenu.html, containing expression data of 1520 transcription factors and cofactors expressed in E9.5, E10.5, and E11.5 mouse embryos --a highly dynamic stage of skeletal myogenesis. This approach implicated 43 genes in regulation of embryonic myogenesis, including a transcriptional repressor, the zinc-finger protein RP58 (also known as Zfp238) [1].


Knockout and knockdown approaches confirmed an essential role for RP58 in skeletal myogenesis. Cell-based high-throughput transfection screening revealed that RP58 is a direct MyoD target. Microarray analysis identified two inhibitors of skeletal myogenesis, Id2 and Id3, as targets for RP58-mediated repression. Consistently, MyoD-dependent activation of the myogenic program is impaired in RP58 null fibroblasts and downregulation of Id2 and Id3 rescues MyoD's ability to promote myogenesis in these cells.


Our combined, multi-system approach reveals a MyoD-activated regulatory loop relying on RP58-mediated repression of muscle regulatory factor inhibitors. We applied our systems approaches to other locomotive tissues research including cartilage and tendon, and revealed novel molecular network regulating joint cartilage development and homeostasis via microRNA-140 [2, 3] and tendon development by Mkx [4].

Authors’ Affiliations

Department of Systems BioMedicine, Tokyo Medical and Dental University
Department of Systems BioMedicine, National Research Institute for Child Health and Development
The Scripps Research Institute


  1. Yokoyama S, Ito Y, Ueno-Kudoh H, Shimizu H, Uchibe K, Albini S, Mitsuoka K, Miyaki S, Kiso M, Nagai A, Hikata T, Osada T, Fukuda N, Yamashita S, Harada D, Mezzano V, Kasai M, Puri PL, Hayashizaki Y, Okado H, Hashimoto M, Asahara H: A systems approach reveals that the myogenesis genome network is regulated by the transcriptional repressor RP58. Dev Cell. 2009, 17: 836-848. 10.1016/j.devcel.2009.10.011.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Miyaki S, Sato T, Inoue A, Otsuki S, Ito Y, Yokoyama S, Kato Y, Takemoto F, Nakasa T, Yamashita S, Takada S, Lotz MK, Ueno-Kudo H, Asahara H: MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev. 2010, 24: 1173-1185. 10.1101/gad.1915510.PubMed CentralView ArticlePubMedGoogle Scholar
  3. Miyaki S, Nakasa T, Otsuki S, Grogan SP, Higashiyama R, Inoue A, Kato Y, Sato T, Lotz MK, Asahara H: MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum. 2009, 60: 2723-2730. 10.1002/art.24745.PubMed CentralView ArticlePubMedGoogle Scholar
  4. Ito Y, Toriuchi N, Yoshitaka T, Ueno-Kudoh H, Sato T, Yokoyama S, Nishida K, Akimoto T, Takahashi M, Miyaki S, Asahara H: The Mohawk homeobox gene is a critical regulator of tendon differentiation. Proc Natl Acad Sci U S A. 2010, 107: 10538-10542. 10.1073/pnas.1000525107.PubMed CentralView ArticlePubMedGoogle Scholar


© Asahara; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.