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Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
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G-CSF Receptor Deletion Amplifies Cortical Bone Dysfunction in Mice With STAT3 Hyperactivation in Osteocytes.
Tsuyoshi Isojima1,2, Emma C Walker1, Ingrid J Poulton1
1St. Vincent's Institute of Medical Research, Fitzroy, Australia.
Summary
Granulocyte-colony-stimulating factor receptor (G-CSFR) deficiency further delays cortical bone maturation by increasing STAT signaling. This leads to impaired bone structure, highlighting G-CSF
Area of Science:
- Bone biology and skeletal development.
- Cellular mechanisms of bone remodeling.
- Molecular signaling pathways in osteocytes.
Background:
- Cortical bone strength relies on its outer shell structure, but consolidation mechanisms are unclear.
- Osteocyte maturation involves SOCS3 suppressing IL-6/STAT3 signaling.
- SOCS3 also suppresses G-CSFR signaling, prompting investigation into G-CSFR's role.
Purpose of the Study:
- To investigate the effect of global G-CSFR (Csf3r) ablation on cortical bone structure in mice lacking SOCS3 in osteocytes.
- To determine if G-CSFR deficiency exacerbates bone maturation defects.
Main Methods:
- Generated Dmp1Cre :Socs3f/f :Csf3r-/- mice by crossing Dmp1Cre :Socs3f/f and Csf3r-/- mice.
- Analyzed bone structure using micro-computed tomography (Micro-CT) and histology.
- Quantified gene expression of bone remodeling and angiogenesis markers via qRT-PCR.
Main Results:
- G-CSFR deletion further delayed cortical consolidation, resulting in porous, low-density bone.
- Histology revealed immature bone, increased osteoclasts, woven bone formation, and elevated vascularization.
- Gene expression analysis showed increased osteoclast, osteoblast, RANKL, and angiogenesis markers.
- Elevated phospho-STAT1/3 and STAT1/3 target genes indicated increased STAT signaling.
Conclusions:
- G-CSFR deficiency promotes STAT1/3 signaling in osteocytes when SOCS3 feedback is absent.
- This promotes angiogenesis, resorption, and formation, delaying cortical bone consolidation.
- G-CSF plays a critical role in replacing trabecular bone with lamellar bone during cortical formation.
