title: Kindlin-2 controls TGF-β signalling and Sox9 expression to regulate chondrogenesis.
abstract: The signals that control skeletogenesis are incompletely understood. Here we show that deleting Kindlin-2 in Prx1-expressing mesenchymal progenitors in mice causes neonatal lethality, chondrodysplasia and loss of the skull vault. Kindlin-2 ablation reduces chondrocyte density by decreasing cell proliferation and increasing apoptosis, and disrupts column formation, thus impairing the formation of the primary ossification center and causing severe limb shortening. Remarkably, Kindlin-2 localizes to not only focal adhesions, but also to the nuclei of chondrocytes. Loss of Kindlin-2 reduces, while the overexpression of Kindlin-2 increases, Sox9 expression. Furthermore, the overexpression of Sox9 restores the defects in chondrogenic differentiation induced by Kindlin-2 deletion in vitro. In addition, Kindlin-2 ablation inhibits TGF-β1-induced Smad2 phosphorylation and chondrocyte differentiation. Finally, deleting Kindlin-2 in chondrocytes directly impairs chondrocyte functions, resulting in progressive dwarfism and kyphosis in mice. These studies uncover a previously unrecognized function for Kindlin-2 and a mechanism for regulation of the chondrocyte differentiation programme and chondrogenesis.
authors.affiliation: 1] Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. [2] Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Hongli
authors.initials: H
authors.lastname: Jiao
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Ka
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Qu
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Deng
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Pingping
authors.initials: P
authors.lastname: Song
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15240, USA.
authors.forename: Deborah L
authors.identifier: 0000000220458807
authors.initials: DL
authors.lastname: Galson
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15240, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Hee-Jeong
authors.initials: HJ
authors.lastname: Im
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: 1] Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen 518055, China. [2] Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Guozhi
authors.initials: G
authors.lastname: Xiao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019902:Chondrocytes / Q000378:metabolism; D020219:Chondrogenesis / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D012863:Skeleton / Q000002:abnormalities; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; D009124:Muscle Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D016212:Transforming Growth Factor beta; C527802:kindlin-2 protein, mouse