Hormonal Regulation of Bone Mineral Homeostasis

Integration of Hormone Action at the Tissue Level
Figure 1 introduces the major hormones PTH, 1,25(OH)₂D₃, and FGF23 regulating serum calcium and phosphate levels through their actions on bone, intestine, and kidney. PTH is secreted by the parathyroid glands. Vitamin D is produced from 7-dehydrocholesterol in the skin by a photochemical reactioninvolving ultraviolet B radiation (UVB) (sun is the natural source of UVB). The liver, among other tissues—including the skin—converts vitamin D to the major circulating form 25 hydroxyvitamin D (25OHD). The kidney is the major source of 1,25(OH)₂D₃ for the circulation, although a variety of tissues, including a number of epithelial and immunoregulatory cells, possess the enzyme CYP27B1, which is capable of converting 25OHD to 1,25(OH)₂D₃. FGF23 is thought to originate primarily from osteoblasts and osteocytes, although the source of this relative newcomer to the list of calciotropic hormones is still under active investigation and other cells express it. Calcium and phosphate enter the blood from the intestine, are excreted by the kidney, and are stored in the body principally in bone. In order to maintain homeostasis, the net absorption of calcium and phosphate by the intestine must be precisely balanced by net excretion of these ions by the kidney.

Absorption of these ions by the gut is not a continuous process, butdepends on dietary intake. The efficiency with which absorption occurs for a given dietary load is the regulated variable. Glomerular filtration of these ions by the kidney is relatively constant and dependent on overall renal function, so the control takes place in adjusting the efficiency with which these ions are reabsorbed from the glomerular filtrate as it passes through the proximal tubule, thick and thin limbs of Henle’s loops (TALH), distal tubule, and collecting ducts. Bone provides the major buffer for maintaining relatively constant blood levels of these ions. This is achieved by balancing bone formation, which deposits these ions in bone with bone resorption, which releases these ions to the blood stream. Although each tissue has distinct mechanisms and molecules by which it contributes to bone mineral homeostasis, some common themes are found, at least at the level of protein families. Therefore, TRPV6 (dominant in intestine) and TRPV5 (dominant in kidney) are highly homologous calcium channels in the apical membranes of their respective epithelial cells and play critical roles in calcium absorption (intestine) and reabsorption (kidney), respectively.¹ Similarly, calbindins are a family of homologous proteins initially thought to play important roles in the intracellular transport of calcium through the epithelia of the intestine and kidney, with different calbindins in these different tissues, although recent data suggest their role in transcellular transport may be limited.^2,3 Different but homologous plasma membrane calcium adenosine triphosphatases (ATPases), calcium pumps (PMCA), reside in the basolateral membranes of the epithelia of the intestine and kidney to transport the calcium out of the cell and into the bloodstream. Finally, different but homologous sodium/phosphate co-transporters reside in the apical membranes of the epithelia of the intestine and kidney to regulate phosphate absorption and reabsorption. ⁴

Little is known about the role, if any, of these protein families in bone. The expression and function of these proteins are highly regulated, in particular by the calciotropic hormones. Not surprisingly, there are sensors in these tissues that, along with hormonal regulation, control these processes. The best studied of these sensors is the calcium-sensing receptor found in the parathyroid gland, bone, intestine, and kidney, among other tissues. ⁵ A sensor for phosphate is less clearly demonstrated, but probably exists in some or all of these tissues. Various hormones act on the tissues by different mechanisms, as I will discuss below. However, their effects are well co-ordinated to ensure an increased supply of bone minerals during periods of growth, steady-state levels during middle life, and gradual loss during aging.

Hormonal and Ionic Feedback Loops
Figure 2 shows the feedback loops that operate among the calciotropic hormones. PTH is the major regulator of 1,25(OH)2D3 production by the kidney. This regulation appears to be genomic and mediated by protein kinase A phosphorylation of transcription factors that act on the proximal region of the CYP27B1 promoter. ⁶ Non-renal sites of 1,25(OH)2D3 production such as the keratinocyte and macrophage do not have PTH receptors, and so their CYP27B1 expression is not regulated by PTH, at least not directly. ⁷ On the other hand, PTH production is inhibited by 1,25(OH)2D3, again at the transcriptional level. ⁸ The relationship between FGF23 and 1,25(OH)2D3 is the reverse, with FGF23 inhibiting CYP27B1 activity and 1,25(OH)2D3 stimulating FGF23 production. ⁹ FGF23 requires both specific FGF receptors (FGFR1c, 3c, and 4) and Klotho as a co-receptor. ¹⁰ To my knowledge, regulation of CYP27B1 expression by FGF23 outside the kidney has not been reported, limited perhaps by the lack of Klotho in these tissues. However, the parathyroid gland expresses both FGFRs and Klotho, and recent studies indicate that FGF23 inhibits PTH production and secretion. ¹¹ PTH may stimulate FGF23 secretion in that serum levels of these hormones correlate in models of hyper-parathyroidism, ¹² but a direct regulation by PTH of FGF23 expression has not been established. In addition to the hormonal feedback loops are the feedback loops involving calcium and phosphate (see Figure 3). Both calcium and phosphate may have direct actions to suppress CYP27B1 activity in the kidney. However, their major influences are likely to be indirect: calcium suppressing CYP27B1 expression by suppressing PTH production and secretion, and phosphate suppressing CYP27B1 expression by stimulating FGF23 production and secretion. Phosphate may also stimulate PTH secretion directly, but this action is less established than the inhibitory effects of calcium on PTH secretion.