Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Region-specific increase in cortical porosity in the adult murine skeleton by inducing STAT3 hyperactivation in osteoblasts and osteocytes (#137)

Natalie YY Koh 1 2 , Narelle E McGregor 1 , Natalie KY Wee 1 2 , Christa Maes 3 , Natalie A Sims 1 2
  1. St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
  2. University of Melbourne, Melbourne, 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, Belgium

Cortical bone becomes more porous with ageing, but the signals responsible are not known. Previous work has shown that high cortical porosity occurs in the developing skeleton when STAT3 (Signal Transducer and Activator of Transcription 3) signalling was elevated in osteoblasts and osteocytes by targeted Socs3 deletion. We sought to determine whether cortical porosity could be increased if Socs3 deletion and STAT3 hyperactivation in osteoblasts and osteocytes was delayed until adulthood.

 

We generated tamoxifen-dependent Socs3-deficient mice with an Ai9.tdTomato fluorescent tag to identify recombination in situ (iDMPCre+.Ai9. Socs3ff). Gene recombination was induced by 4 doses of 20mg/kg tamoxifen between 12- and 14-weeks of age in female iDMPCre+.Ai9. Socs3f/f mice and controls (iDMPCre+.Ai9). Bone-specific Socs3 recombination was confirmed by PCR. By cryo-histology, ~100% of trabecular osteocytes were tdTomato+. In cortical bone, Cre-mediated recombination was region-specific: at 14- and 26-weeks, ~80% of metaphyseal osteocytes were tdTomato+, but only ~50% were tdTomato+ in the diaphysis.

 

Micro-CT analysis showed that tamoxifen treatment in control (iDMPCre+.Ai9) femora induced a transient increase in metaphyseal trabecular bone volume and cortical porosity which both normalized by 26 weeks. In iDMPCre+.Ai9. Socs3ff femora at 16-, 20-, 26- and 32-weeks, cortical porosity and low-density cortical bone were significantly increased at the metaphysis, by ~400% and ~20% respectively, compared to tamoxifen-treated controls. Histology revealed greater bone resorption and formation, indicating increased remodelling in the metaphysis that was not observed at the diaphysis.

 

These data indicate that Socs3 deletion induced in a young adult skeleton in osteoblasts and osteocytes increases cortical porosity and reduces its consolidation, but only in regions with the highest levels of recombination that undergo greater cortical remodelling. This suggests that more mature regions of the murine cortex, like the diaphysis, are protected from any increase in cortical porosity caused by high STAT3 signalling in osteoblasts and osteocytes.