title: Disruption of glucocorticoid signaling in chondrocytes delays metaphyseal fracture healing but does not affect normal cartilage and bone development.
abstract: States of glucocorticoid excess are associated with defects in chondrocyte function. Most prominently there is a reduction in linear growth but delayed healing of fractures that require endochondral ossification to also occur. In contrast, little is known about the role of endogenous glucocorticoids in chondrocyte function. As glucocorticoids exert their cellular actions through the glucocorticoid receptor (GR), we aimed to elucidate the role of endogenous glucocorticoids in chondrocyte function in vivo through characterization of tamoxifen-inducible chondrocyte-specific GR knockout (chGRKO) mice in which the GR was deleted at various post-natal ages. Knee joint architecture, cartilage structure, growth plates, intervertebral discs, long bone length and bone micro-architecture were similar in chGRKO and control mice at all ages. Analysis of fracture healing in chGRKO and control mice demonstrated that in metaphyseal fractures, chGRKO mice formed a larger cartilaginous callus at 1 and 2 week post-surgery, as well as a smaller amount of well-mineralized bony callus at the fracture site 4 week post-surgery, when compared to control mice. In contrast, chondrocyte-specific GR knockout did not affect diaphyseal fracture healing. We conclude that endogenous GC signaling in chondrocytes plays an important role during metaphyseal fracture healing but is not essential for normal long bone growth.
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia.
authors.forename: Jinwen
authors.initials: J
authors.lastname: Tu
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia.
authors.forename: Holger
authors.initials: H
authors.lastname: Henneicke
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia.
authors.forename: Shihani
authors.initials: S
authors.lastname: Stoner
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Tegan L
authors.initials: TL
authors.lastname: Cheng
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Aaron
authors.initials: A
authors.lastname: Schindeler
authors.affiliation: Tissue Department of Biochemistry, Rush University Medical Center, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: Institute of General Zoology and Endocrinology, University of Ulm, Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Tuckermann
authors.affiliation: Department of Endocrinology & Metabolism, Concord Hospital, Sydney, Australia.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cooper
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia; Department of Endocrinology & Metabolism, Concord Hospital, Sydney, Australia.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Seibel
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia. Electronic address: h.zhou@sydney.edu.au.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001846:Bone Development / Q000502:physiology*; D002356:Cartilage / Q000254:growth & development* / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism*; D017102:Fracture Healing / Q000502:physiology*; D005938:Glucocorticoids / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology
chemical_list: D005938:Glucocorticoids
keywords: Cartilage; Chondrocyte; Diaphyseal fracture; Glucocorticoids; Growth; Metaphyseal fracture