Fig 2.

During a positive calcium balance (left panel), normal serum calcium concentrations allow proper bone mineralization. Transgenic models with Vdr inactivation in osteoprogenitors (Osx‐Cre^{( 51 )}) or in mature osteoblasts and osteocytes (Dmp1‐Cre^{( 26 )}) display normal mineral and bone homeostasis. Vdr knockdown in immature osteoblasts (Col1a1‐Cre^{( 49 )}) induces bone mass, whereas Vdr overexpression in mature osteoblasts (Osteocalcin‐Cre^{( 48} , ^{50 )}) also leads to an elevated bone mass. Vdr inactivation in osteoclast precursors (LysM‐Cre^{( 57 )}) does not affect bone homeostasis, whereas Vdr‐silencing in mature osteoclasts (Ctsk‐Cre) has either no effect^{( 51 )} or leads to a slight reduction in bone mass.^{( 58 )} During a negative calcium balance (right panel), insufficient intestinal calcium absorption leads to increased PTH and 1,25(OH)₂D₃ levels, which stimulate RANKL expression by osteoblasts and enhance bone resorption.^{( 52 )} Moreover, 1,25(OH)₂D₃ inhibits bone mineralization by directly inducing the expression of mineralization inhibitors.^{( 26 )} Elevated resorption and decreased mineralization both contribute to the maintenance of normocalcemia. Mice with selective Vdr knockdown in mature osteoclasts (Ctsk‐Cre^{( 59 )}) experience a greater bone loss during a negative calcium balance. (Figure created with BioRender.com.)