Deleting Suppressor of Cytokine Signaling-3 in chondrocytes reduces bone growth by disrupting mitogen-activated protein kinase signaling
- Author(s)
- Liu, X; D'Cruz, AA; Hansen, J; Croker, BA; Lawlor, KE; Sims, NA; Wicks, IP;
- 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
- Research Division(s)
- Inflammation
- PubMed ID
- 31176017
- Publisher's Version
- https://doi.org/10.1016/j.joca.2019.05.018
- NHMRC Grants
- NHMRC/1023407, NHMRC/1016647,
- Terms of Use/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