A role for the Calcitonin respetor to limit bone loss during lactation in female mice by inhibiting osteocytic osteolysis

Abstract

During lactation, the large transfer of calcium from the mother to the milk is primarily sourced from the maternal skeleton. To determine whether the calcitonin receptor (CTR) plays a physiological role to protect the skeleton from excessive resorption during lactation, we assessed the maternal skeleton of Global CTRKO and littermate control mice at the end of lactation (P21). MicroCT analyses showed no effect on trabecular or cortical bone in the distal femur and L1 vertebra of maternal Global CTR deletion at the end of lactation in Global CTRKOs, compared to controls. Bone resorption, as assessed by osteoclast number and activity at the end of lactation, was unaffected by maternal CTR deletion. Cathepsin K, carbonic anhydrase 2, matrix metalloproteinase 13 and RANKL mRNA levels, however, were markedly elevated by 3 to 6.5 fold in whole bone of lactating Global CTRKO females. Since these genes have been shown to be up-regulated in osteocytes during lactation when osteocytes resorb their surrounding bone matrix, together with their reported expression of the CTR, we determined osteocyte lacunar area in cortical bone. Following lactation, the top 20% of osteocyte lacunar area in Global CTRKOs was 10% larger than the top 20% in controls. These data are consistent with an increased osteocytic osteolysis in Global CTRKOs during lactation, which is further supported by the increased serum calcium observed in Global CTRKOs following lactation. These results provide evidence for a physiological role for the CTR to protect the maternal skeleton during lactation by a direct action on osteocytes to inhibit osteolysis.