Deleting Suppressor of Cytokine Signaling-3 in chondrocytes reduces bone growth by disrupting mitogen-activated protein kinase signaling
Details
Publication Year 2019-10, Volume 27, Issue #10, Page 1557-1563
Journal Title
Osteoarthritis Cartilage
Publication Type
Journal Article
Abstract
OBJECTIVE: To investigate the impact of deleting Suppressor of Cytokine Signaling-3 (SOCS3) in chondrocytes during murine skeletal development. METHOD: Mice with a conditional Socs3 allele (Socs3(fl/fl)) were crossed with a transgenic mouse expressing Cre recombinase under the control of the type II collagen promoter (Col2a1) to generate Socs3(Delta/Deltacol2) mice. Skeletal growth was analyzed over the lifespan of Socs3(Delta/Deltacol2) mice and controls by detailed histomorphology. Bone size and cortical bone development was evaluated by micro-computed tomography (micro-CT) Growth plate zone width, chondrocyte proliferation and apoptosis were assessed by immunofluorescence staining for Ki67 and TUNEL. Fibroblast growth factor receptor-3 (FGFR3) signaling in the growth plate was assessed by immunohistochemistry, while the effect of SOCS3 overexpression on FGFR3-driven pMAPK signaling in HEK293T cells was evaluated by Western blot. RESULTS: Socs3(Delta/Deltacol2) mice of both sexes were consistently smaller compared to littermate controls throughout life. This phenotype was due to reduced long bone size, poor cortical bone development, reduced Ki67(+) proliferative chondrocytes and decreased proliferative zone width in the growth plate. Expression of pMAPK, but not pSTAT3, was increased in the growth plates of Socs3(Delta/Deltacol2) mice relative to littermate controls. Overexpression of FGFR3 in HEK293T cells increased Fibroblast Growth Factor 18 (FGF18)-dependent MAPK phosphorylation, while concomitant expression of SOCS3 reduced FGFR3 expression and abrogated MAPK signaling. CONCLUSION: Our results suggest a potential role for SOCS3 in growth plate chondrocyte proliferation by regulating FGFR3-dependent MAPK signaling in response to FGF18.
Publisher
Elsevier
WEHI Research Division(s)
Inflammation
PubMed ID
31176017
NHMRC Grants
NHMRC/1023407 NHMRC/1016647
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2019-06-20 10:18:10
Last Modified: 2019-10-11 03:34:06
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