A Role for the Calcitonin Receptor 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 CTR knockout (CTRKO) and littermate control mice at the end of lactation (postnatal day 21). Micro-computed tomography 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 CTRKO mice compared with that in control mice. 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 receptor activator of nuclear factor-κB ligand mRNA levels, however, were markedly elevated by 3- to 6.5-fold in whole bone of lactating global CTRKO females. Because 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 the osteocyte lacunar area in cortical bone. After lactation, the top 20% of osteocyte lacunar area in global CTRKO mice was 10% larger than the top 20% in control mice. These data are consistent with an increased osteocytic osteolysis in global CTRKO mice during lactation, which is further supported by the increased serum calcium observed in global CTRKO mice after 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.

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

“…During lactation these conditionally deleted Ctr null mice show a greater increase in osteocyte lacunar size compared with WT, suggesting that loss of calcitonin signaling leads to increased osteocytic osteolysis (187). However, there were no significant differences in bone structure by microCT or histomorphometry between Ctr nulls and WT (187). Moreover, prolactin was significantly reduced, which is the opposite of what was expected given that targeted overexpression of calcitonin in the pituitary, and pharmacological treatment with calcitonin, both reduce prolactin.…”

“…This results in Ͼ90% but not 100% loss of CTR expression in kidneys and osteoclasts; expression in other tissues relevant to lactation, especially mammary tissue and pituitary, were not assessed. During lactation these conditionally deleted Ctr null mice show a greater increase in osteocyte lacunar size compared with WT, suggesting that loss of calcitonin signaling leads to increased osteocytic osteolysis (187). However, there were no significant differences in bone structure by microCT or histomorphometry between Ctr nulls and WT (187).…”

The Role of the Osteocyte in Bone and Nonbone Disease

“…This study shows that healthy osteocytes can both remove and replace their perilacunar matrix thereby playing a role in mineral homeostasis during calcium demanding conditions. Recently it has been shown that the Calcitonin Receptor may also play a role by inhibiting perilacunar remodeling with lactation 41 .…”

Osteocytes and Skeletal Pathophysiology

“…The expression of genes known to be utilized by osteoclasts to remove bone, including tartrate-resistant acid phosphatase (TRAP) and cathepsin K, carbonic anhydrase 2 and matrix metalloproteinases is elevated in osteocytes from lactating mice (55–57). Furthermore, recent work demonstrated that global deletion of the calcitonin receptor leads to increased osteocytic, but not osteoclastic, osteolysis during lactation, providing the first evidence for a physiological role of the calcitonin receptor to protect the maternal skeleton from bone loss during lactation by direct actions on osteocytes (58). Although the physiologic implications of these observations remain to be determined, this data suggests that, as previously described for phosphate metabolism, osteocytes also contribute to calcium mobilization and mineral homeostasis through perilacunar remodeling as has been proposed earlier(1;59).…”