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

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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.

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  • 16 October 2019

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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).

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Authors and Affiliations

  1. Sensory and Motor System Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Takeshi Oichi, Yuki Taniguchi, Kazuhito Soma, Yasushi Oshima, Sakae Tanaka & Taku Saito

  2. Bone and Cartilage Regenerative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Fumiko Yano, Ryota Chijimatsu & Taku Saito

  3. Division of Oral Anatomy, Department of Human Development and Fostering, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, 350-0283, Saitama, Japan

    Yoshifumi Mori

  4. Department of Biochemistry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Joo-ri Kim-Kaneyama

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  1. Takeshi Oichi
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Oichi, T., Taniguchi, Y., Soma, K. et al. Adamts17 is involved in skeletogenesis through modulation of BMP-Smad1/5/8 pathway. Cell. Mol. Life Sci. 76, 4795–4809 (2019). https://doi.org/10.1007/s00018-019-03188-0

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