Increased STAT3 (Signal Transducer and Activator of Transcription 3) or VEGF (Vascular Endothelial Growth Factor) signalling in the osteoblast lineage leads to greater cortical porosity in the adult skeleton — ASN Events
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Increased STAT3 (Signal Transducer and Activator of Transcription 3) or VEGF (Vascular Endothelial Growth Factor) signalling in the osteoblast lineage leads to greater cortical porosity in the adult skeleton (#4)

Natalie Koh 1 2 3 , Narelle McGregor 2 , Marion Mesnieres 4 , Seppe Melis 4 , Ruben Cardoen 4 , Elena Nefyodova 4 , Christa Maes 4 , Natalie Sims 1 2 5
  1. University of Melbourne, Melbourne, VIC, Australia
  2. St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
  3. Laboratory of Skeletal Cell Biology and Physiology (SCEBP), Skeletal Biology and Engineering Research Center (SBE), Department of Development and Regeneration, KU Leuven, Leuven, Belgiu,m
  4. Laboratory of Skeletal Cell Biology and Physiology (SCEBP), Skeletal Biology and Engineering Research Center (SBE), Department of Development and Regeneration, KU Leuven, Leuven, Belgium
  5. Mary Mackillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia

Although cortical porosity increases with aging and is a major contributor to fracture risk, the signals responsible are unknown. We previously reported that increasing STAT3 signalling in osteoblasts and osteocytes, by constitutively deleting the Suppressor of Cytokine Signalling 3 (SOCS3), led to a highly porous skeleton with increased vascularisation and VEGF mRNA levels in juvenile mice.

Here, we tested whether cortical porosity could be induced in the adult skeleton by adult-onset deletion of SOCS3 in osteoblasts/osteocytes. We generated mice (iDMPCreSocs3f/f) with osteoblast/osteocyte-targeted Ai9/tdTomato fluorescence and SOCS3 deletion, both induced by tamoxifen administration from 12-14 weeks of age. Longitudinal micro-CT analysis at 16, 20, and 26 weeks of age detected 5-fold greater femoral cortical porosity in iDMPCreSocs3f/f mutants compared with tamoxifen-treated genetic controls. This was initially restricted to the metaphysis but, by 32-weeks, greater porosity (~2.4-fold) also emerged at the diaphysis. Histology and double calcein labelling revealed greater intracortical and endocortical resorption and formation in iDMPCreSocs3f/f mice compared to controls. 3D-confocal microscopy showed that the cortical pores contained blood vessels lined with genetically-targeted tdTomato-positive cells.

To assess the effect of increased vascularization on cortical porosity, we next analysed mice with increased expression of VEGFA in the osteoblast lineage (dOsxCreVegfacTg) with a green fluorescent protein (GFP) tag, as previously described (Mesnieres et al., Cell Rep. 2021). Overexpression was delayed by doxycycline-mediated OsxCre-suppression until E13.5 to ensure perinatal survival. At 32 weeks of age, these mice had ~20-fold greater cortical porosity than controls in the metaphysis and ~10-fold greater in the diaphysis. Bone resorption and formation were increased, at a higher level than in the iDMPCreSocs3f/f model, and along the full length of the bone. Similar to theiDMPCreSocs3f/f model, the cortical pores contained blood vessels lined with osteoblast progenitors (Osx-GFP+).  

These data indicate that increased STAT3 or VEGFA signalling in osteoblast lineage cells triggers cortical pore expansion; this includes increased bone formation, resorption, vascularisation, and presence of mutant intracortical cells associated with the vasculature. This suggests common local mechanisms are used and that inhibiting either, or both, pathways could prevent age-related increases in cortical porosity and bone fragility.