Plenary Poster 30th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2020

Can circulating Wnt antagonist DKK1 alter bone mass by endocrine signalling? (#21)

Ya Xiao 1 , Sindhu T Mohanty 1 , Michelle M McDonald 1 2 , Aaron Schindeler 3 4 , David G Little 3 4 , Peter I Croucher 1 2 , Paul A Baldock 1 2 5
  1. Healthy Ageing,Bone Biology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
  3. Kids Research Institute, The children’s Hospital Westmead, Westmead, NSW, Australia
  4. University of Sydney, Camperdown, NSW, Australia
  5. School of Medicine Sydney, University of Notre Dame Australia, Darlinghurst, NSW, Australia

Osteoblasts and bone marrow stromal cells modulate bone mass through secretion of the Wnt inhibitor DKK1, which negatively regulates osteoblast differentiation. Increased levels of circulating Dkk1 have been correlated with post-menopausal bone loss. The extent to which serum Dkk1 levels represent their functional regulation of bone anabolism or provide a biomarker of local bone changes remains to be determined. We aimed to examine the effect of altered local Dkk1 production on systemic bone accrual.

Limb-specific DKK1 KO mice were generated using Prxx1 Cre mice; where Dkk1 was deleted in the appendicular skeleton, but retained in the axial skeleton and circulation. Prx1/Dkk1 KO and control WT/Dkk1 floxed mice were culled at 10 and 16 weeks of age and lumbar vertebrae and femurs assessed by DXA and microCT.

DXA in Prx1/Dkk1 KO revealed greater limb bone mineral density (BMD) in male (17.4%)and female (11%) mice at 10 weeks of age and male (13.6%) and female (5.3%) at 16 week of age compared to controls (p<0.001). In contrast, vertebral BMD was not different to control for both sexes and ages.

MicroCT confirmed these findings, with greater distal femoral metaphyseal trabecular bone volume (BV/TV) in male (27.9%) and female (81.2%) mice at 10 weeks, and male (23%) and female (67.1%) at 16 weeks compared to controls (p<0.001). These changes were a result of increased trabecular number with no changes in trabecular or femoral shaft cortical thickness. Again, vertebral trabecular BV/TV was not different to control for both sexes and ages.

We have provided evidence that loss of Dkk1 in the appendicular skeleton increased bone mass, whereas the axial skeleton was not impacted. In conclusion our results indicate that circulating levels of Dkk1 do not reflect the local production and therefore activity of this potent Wnt antagonist.