The influence of sclerostin-Wnt signaling on bone and mineral metabolism during lactation and weaning

Abstract

Lactation is a state of rapid bone loss for milk production; however, the maternal bone undergoes a rapid remineralization after weaning. Sclerostin, encoded by the gene SOST, is exclusively secreted from osteocytes and has important regulator of bone remodeling by inhibiting Wingless and Int-1 (Wnt) signaling by binding to extracellular domain of low-density lipoprotein receptor-related protein 5/6 (LRP5/6). However, the role of sclerostin-Wnt signaling for controlling bone remodeling during lactation and weaning has not been studied. In this study, we hypothesized that sclerostin related with Wnt signaling would affect bone metabolism and microstructures during lactation and weaning, and pregnancy and lactation associated osteoporosis (PLO) would be related with mutation of Wnt signaling pathway. We used whole-exome sequencing (WES) to reveal associations between genetic variants and PLO patients with multiple vertebral fractures. We also used dual energy X-ray absorptiometry (DXA), micro-computed tomography (µCT) to evaluate and compared the effect of sclerostin on bone mass and microarchitectures of wild type and DMP1-Sost transgenic mice, in which sclerostin is overexpressed by osteocyte. As a result, WES showed 8 out of 12 patients showed LRP5/6 mutation encoding the extra-cellular signaling domain of LRP5/6, which sclerostin or Wnt signaling agonists bind to. In animal study, lactation significantly lead to decreased spine and femur bone mineral density (BMD) at 1-week and 3-week of lactation; especially cortical microstructure (cross-sectional thickness and cross-sectional area) at mid-shaft femur were significantly deteriorated. At 2-week after weaning, incomplete recovery of femur BMD and cortical microstructure at mid-shaft femur in both wild and DMP1-Sost mice; however, spine BMD and trabecular microstructures at distal femur were recovered only in wild type mice, suggesting that sclerostin-overexpression would affect bone formation, especially in trabecular dominant bone compartment during weaning period. In conclusion, LRP5/6 mutations related with Wnt pathway, would be one of the plausible risk factors of failure of maternal bone mineral adaptation to severe bone loss during lactation and weaning contributing to PLO. To activate Wnt signaling pathway during lactation and after weaning for compensation of bone loss, control of sclerostin level by osteocytes would be important to maintain bone mineral metabolism.