Figure 10. Schematic representation of the relationship between osteocytic osteolysis, bone remodeling, and calcium metabolism during lactation in mice in the presence or absence of Ctsk in osteocytes.

(A) In the presence of Ctsk in osteocytes (control lactating mice), the changes induced by the lactating mammary gland, including increased secretion of PTHrP, switch the osteocytes to the resorbing mode, increasing TRAP activity and Ctsk expression and leading to increased perilacunar resorption (PLR) and lacunar enlargement. These changes in the osteocyte microenvironment lead to an increase in PTHrP and the Rankl/Opg ratio, thereby increasing osteoclastogenesis, bone resorption, and serum calcium. This increase in serum calcium is also secondary to higher PTHrP and 1,25(OH)₂D acting on the kidney and the gut, resulting in both calcium supply to the milk and repression of endogenous PTH secretion. (B) In the absence of Ctsk in osteocytes (Ctsk^ocy lactating mice), although the changes induced in the mammary gland by lactation increase TRAP activity and Pthrp in osteocytes, deletion of Ctsk prevents PLR, enlargement of the lacuna, and an increase in the Rankl/Opg ratio and osteoclastogenesis. The lack of osteocytic osteolysis and osteoclastogenesis limits the supply of calcium to serum; this is sensed by the parathyroid gland, which continues to secrete PTH at prelactation levels and, together with PTHrP, enhances 1,25(OH)₂D levels and thus calcium absorption from the gut, compensating for the limited supply of calcium coming from bone and ensuring appropriate calcium levels in the blood and milk.