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Adamts17 is involved in skeletogenesis through modulation of BMP-Smad1/5/8 pathway

  • Takeshi Oichi
  • Yuki Taniguchi
  • Kazuhito Soma
  • Yasushi Oshima
  • Fumiko Yano
  • Yoshifumi Mori
  • Ryota Chijimatsu
  • Joo-ri Kim-Kaneyama
  • Sakae Tanaka
  • Taku SaitoEmail author
Original Article
  • 62 Downloads

Abstract

Fibrillin microfibrils are ubiquitous elements of extracellular matrix assemblies that play crucial roles in regulating the bioavailability of growth factors of the transforming growth factor beta superfamily. Recently, several “a disintegrin and metalloproteinase with thrombospondin motifs” (ADAMTS) proteins were shown to regulate fibrillin microfibril function. Among them, ADAMTS17 is the causative gene of Weill-Marchesani syndrome (WMS) and Weill-Marchesani-like syndrome, of which common symptoms are ectopia lentis and short stature. ADAMTS17 has also been linked to height variation in humans; however, the molecular mechanisms whereby ADAMTS17 regulates skeletal growth remain unknown. Here, we generated Adamts17-/- mice to examine the role of Adamts17 in skeletogenesis. Adamts17-/- mice recapitulated WMS, showing shorter long bones, brachydactyly, and thick skin. The hypertrophic zone of the growth plate in Adamts17-/- mice was shortened, with enhanced fibrillin-2 deposition, suggesting increased incorporation of fibrillin-2 into microfibrils. Comprehensive gene expression analysis of growth plates using laser microdissection and RNA sequencing indicated alteration of the bone morphogenetic protein (BMP) signaling pathway after Adamts17 knockout. Consistent with this, phospho-Smad1 levels were downregulated in the hypertrophic zone of the growth plate and in Adamts17-/- primary chondrocytes. Delayed terminal differentiation of Adamts17-/- chondrocytes, observed both in primary chondrocyte and primordial metatarsal cultures, and was prevented by BMP treatment. Our data indicated that Adamts17 is involved in skeletal formation by modulating BMP-Smad1/5/8 pathway, possibly through inhibiting the incorporation of fibrillin-2 into microfibrils. Our findings will contribute to further understanding of disease mechanisms and will facilitate the development of therapeutic interventions for WMS.

Keywords

Adamts17 Fibrillin Microfibril Skeletal formation 

Notes

Acknowledgements

We thank J. Sugita for technical assistance. This study was supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (16K10810, 17K10924, 17H04311).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All experiments performed in this study comply with the current laws of Japan.

Supplementary material

18_2019_3188_MOESM1_ESM.docx (1.9 mb)
Supplementary file1 (DOCX 1979 kb)
18_2019_3188_MOESM2_ESM.docx (28 kb)
Supplementary file2 (DOCX 27 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Takeshi Oichi
    • 1
  • Yuki Taniguchi
    • 1
  • Kazuhito Soma
    • 1
  • Yasushi Oshima
    • 1
  • Fumiko Yano
    • 2
  • Yoshifumi Mori
    • 3
  • Ryota Chijimatsu
    • 2
  • Joo-ri Kim-Kaneyama
    • 4
  • Sakae Tanaka
    • 1
  • Taku Saito
    • 1
    • 2
    Email author
  1. 1.Sensory and Motor System MedicineThe University of TokyoTokyoJapan
  2. 2.Bone and Cartilage Regenerative Medicine, Faculty of MedicineThe University of TokyoTokyoJapan
  3. 3.Division of Oral Anatomy, Department of Human Development and FosteringMeikai University School of DentistrySakadoJapan
  4. 4.Department of BiochemistryShowa University School of MedicineTokyoJapan

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