RRC ID 56702
Author Oichi T, Taniguchi Y, Soma K, Oshima Y, Yano F, Mori Y, Chijimatsu R, Kim-Kaneyama JR, Tanaka S, Saito T.
Title Adamts17 is involved in skeletogenesis through modulation of BMP-Smad1/5/8 pathway.
Journal Cell Mol Life Sci
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.
Volume 76(23)
Pages 4795-4809
Published 2019-12-1
DOI 10.1007/s00018-019-03188-0
PII 10.1007/s00018-019-03188-0
PMID 31201465
MeSH ADAMTS Proteins / genetics ADAMTS Proteins / physiology* Animals Bone Morphogenetic Proteins / metabolism* Bone Morphogenetic Proteins / pharmacology Cell Differentiation / drug effects Cells, Cultured Chondrocytes / cytology Chondrocytes / metabolism Fibrillin-2 / metabolism Mice Mice, Inbred C57BL Mice, Knockout Microfibrils / metabolism Muscle, Skeletal / growth & development* Muscle, Skeletal / pathology Signal Transduction* Skin / physiopathology Smad1 Protein / metabolism Smad5 Protein / metabolism Smad8 Protein / metabolism Weill-Marchesani Syndrome / metabolism Weill-Marchesani Syndrome / pathology Weill-Marchesani Syndrome / veterinary
IF 7.014
Times Cited 3
Mice RBRC01828