title: Noggin resistance contributes to the potent osteogenic capability of BMP9 in mesenchymal stem cells.
abstract: Mesenchymal stem cells (MSCs) are multipotent progenitors and can differentiate into osteogenic, chondrogenic, and adipogenic lineages. Bone morphogenetic proteins (BMPs) play important roles in stem cell proliferation and differentiation. We recently demonstrated that BMP9 is a potent but less understood osteogenic factor. We previously found that BMP9-induced ectopic bone formation is not inhibited by BMP3. Here, we investigate the effect of BMP antagonist noggin on BMP9-induced osteogenic differentiation. BMP antagonists noggin, chording, gremlin, follistatin, and BMP3 are highly expressed in MSCs, while noggin and follistatin are lowly expressed in more differentiated pre-osteoblast C2C12 cells. BMP9-induced osteogenic markers and matrix mineralization are not inhibited by noggin, while noggin blunts BMP2, BMP4, BMP6, and BMP7-induced osteogenic markers and mineralization. Likewise, ectopic bone formation by MSCs transduced with BMP9, but not the other four BMPs, is resistant to noggin inhibition. BMP9-induced nuclear translocation of Smad1/5/8 is not affected by noggin, while noggin blocks BMP2-induced activation of Smad1/5/8 in MSCs. Noggin fails to inhibit BMP9-induced expression of downstream targets in MSCs. Thus, our results strongly suggest that BMP9 may effectively overcome noggin inhibition, which should at least in part contribute to BMP9's potent osteogenic capability in MSCs.
authors.affiliation: Stem Cell Biology and Therapy Laboratory of the Key Laboratory for Pediatrics Co-Designated by Chinese Ministry of Education, Department of Pediatric Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, 60637.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Siqi
authors.initials: S
authors.lastname: Hong
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Jiye
authors.initials: J
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Bi
authors.forename: Yun
authors.initials: Y
authors.lastname: He
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Guoxin
authors.initials: G
authors.lastname: Nan
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Su
authors.forename: Gaohui
authors.initials: G
authors.lastname: Zhu
authors.forename: Ruidong
authors.initials: R
authors.lastname: Li
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zhang
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Kong
authors.forename: Wei
authors.initials: W
authors.lastname: Shui
authors.forename: Ningning
authors.initials: N
authors.lastname: Wu
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: He
authors.forename: Xian
authors.initials: X
authors.lastname: Chen
authors.forename: Hue H
authors.initials: HH
authors.lastname: Luu
authors.forename: Rex C
authors.initials: RC
authors.lastname: Haydon
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Shi
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Qin
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D010012:Osteogenesis; D015398:Signal Transduction; D051785:Smad Proteins / Q000502:physiology; D000099176:Noggin Protein
chemical_list: D000469:Alkaline Phosphatase; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D051785:Smad Proteins; D000099176:Noggin Protein; C525887:GDF2 protein, human
keywords: BMP signaling; BMP9; TGFβ/BMP antagonist; mesenchymal stem cells; osteogenic differentiation