E-Poster Presentation ESA-SRB-ANZBMS 2021

Carbamazepine does not rescue the osteogenesis imperfecta bone phenotype in Col1a2+/G610C mice but increases fragility in healthy bones (#702)

Martha Blank 1 2 , Narelle E McGregor 1 , Lynn Rowley 3 , Louise HW Kung 3 , Blessing Crimeen-Irwin 1 , Emma C Walker 1 , Ingrid J Poulton 1 , Shireen R Lamande 3 4 , Natalie A Sims 1 2 , John F Bateman 3 4
  1. Bone Cell Biology and Disease Unit, St. Vincent’s Institute of Medical Research, Melbourne, Victoria, Australia
  2. Department of Medicine, The University of Melbourne, St. Vincent’s Hospital, Melbourne, Victoria, Australia
  3. Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
  4. Department of Paediatric, The University of Melbourne, Melbourne, Victoria, Australia

The most common osteogenesis imperfecta (OI) mutations are in the collagen I genes, COL1A1 and COL1A2. The mutations cause collagen misfolding and intracellular retention, and ultimately, bone matrix defects. In a mouse chondrodysplasia model caused by a collagen X misfolding/aggregation mutation, stimulating autophagy and proteasomal degradation pathways with the drug carbamazepine (CBZ) reduced both the protein aggregates and the dwarfism severity. CBZ is now in clinical trials for collagen X chondrodysplasia. We reasoned that CBZ might improve OI through a similar mechanism, so we tested CBZ treatment in the Col1a2+/G610C OI mouse model, in which collagen I misfolding and intracellular retention underlying pathology.

Three week old male Col1a2+/G610C mice and wildtype littermates were gavage-fed CBZ for 3 weeks (escalating to 250 mg/kg/day) followed by a 3-week CBZ slow release implant (250 mg/kg/day).

Micro-computed tomography showed Col1a2+/G610C femora were 11% narrower than wildtype littermates. While CBZ did not increase bone width in Col1a2+/G610C mice, it significantly reduced bone width (by 7%) in wild type mice.

In 3-point-bending tests, Col1a2+/G610C bones were ~60% weaker than wildtype bones. CBZ failed to improve this. Instead, CBZ-treated wildtype bones were ~25% weaker than wildtype controls. This was explained by the narrower width, not by material quality, since no strength defect was present when corrected for bone size. This indicates that CBZ increases bone fragility in wildtype mice by limiting bone growth.

Bone composition assessment by Fourier transform infrared spectroscopy confirmed a greater mineral:matrix ratio in Col1a2+/G610C bones than wildtypes. CBZ did not affect wildtype or Col1a2+/G610C bone composition.

These data indicate that CBZ does not improve bone mass, strength or quality in Col1a2+/G610C osteogenesis imperfecta. However, CBZ increases fragility in healthy bone by suppressing bone growth. This suggests CBZ treatment could negatively impact bone growth in children taking CBZ as an anti-epileptic medication.