Endocrine functions of bone in mineral metabolism regulation

Abstract

Given the dramatic increase in skeletal size during growth, the need to preserve skeletal mass during adulthood, and the large capacity of bone to store calcium and phosphate, juxtaposed with the essential role of phosphate in energy metabolism and the adverse effects of hyperphosphatemia, it is not surprising that a complex systems biology has evolved that permits cross-talk between bone and other organs to adjust phosphate balance and bone mineralization in response to changing physiological requirements. This review examines the newly discovered signaling pathways involved in the endocrine functions of bone, such as those mediated by the phosphaturic and 1,25(OH)2D-regulating hormone FGF23, and the broader systemic effects associated with abnormalities of calcium and phosphate homeostasis.

Figure 1. Interrelationships among FGF23, PTH, 1,25(OH)₂D, and Klotho.

(A) The PTH/1,25(OH)₂D axis. The principal function of the PTH/1,25(OH)₂D axis is to regulate calcium homeostasis. Decrements in serum calcium levels stimulate PTH secretion by the PTG, which targets the kidney to reduce urinary calcium excretion, stimulate 1^α-hydroxylase activity, and enhance the fractional excretion of phosphate (PO₄), and targets bone to increase the efflux of calcium and phosphate. The resulting increase in 1,25(OH)₂D targets the gastrointestinal tract to increase dietary absorption of calcium, which suppresses PTH. (B) The FGF23/Klotho axis. FGF23 produced by bone principally targets the kidney, leading to reductions in serum phosphate and 1,25(OH)₂D levels by stimulating the fractional excretion of phosphate and reducing 1^α-hydroxylase activity. The receptor for FGF23 in the kidney is a Klotho:FGFR1 complex located in the distal tubule. There may be a distal-to-proximal feedback mechanism that mediates the effects of FGF23 on the proximal tubule. FGF23 also decreases the kidney expression of Klotho, which diminishes renal tubular calcium reabsorption via its interactions with transient receptor potential cation channel, subfamily V, member 5 (TRPV5). FGF23 may also directly target the PTG to reduce PTH secretion. FGF23 is the principal phosphaturic hormone and may function to counter the hypercalcemic and hyperphosphatemic effects of excess 1,25(OH)₂D through reductions in PTH and elevations in FGF23 levels.

Figure 2. Hypothetical model of FGF23 regulation.

(A) FGF23 regulation in wild-type osteocytes. FGF23 expression in wild-type osteocytes is low due to putative suppressive signals. DMP1 is processed by BMP1/Tolloid-like metalloproteinases to create N- and C-terminal fragments. The model proposes that the C terminus of DMP1 suppresses FGF23 through its binding to PHEX via the ASARM motif and to integrins via the RGD site as well as facilitates mineralization of matrix. In addition, DMP1 is known to have direct transcriptional activities. Putative chondrocyte-derived and unknown systemic factors also suppress FGF23 as described in the text. In addition, FGF23 undergoes posttranslational processing to inactive N- and C-terminal fragments by yet-to-be defined subtilisin-like proprotein convertases (SPCs). (B) Potential mutations and pathways leading to increased FGF23 production. DMP1 and PHEX mutations may indirectly regulate FGF23 promoter activity through the accumulation in the extracellular matrix of an unknown FGF23-stimulating factor or through direct effects on osteocyte function. Loss of PHEX or DMP1 might also permit integrin interactions with FGFRs, leading to FGFR-mediated increases in FGF23 production. Other phosphaturic factors, such as sFRPs (by interfering with DMP1 processing), FGF7 (through activation of FGRs), and MEPE (through competition with DMP1 for PHEX binding [not shown]) may stimulate FGF23 through common pathways. In addition, known mutations of FGF23 that prevent degradation as well as theoretical mutations in SPCs that degrade FGF23 and/or indirectly modulate DMP1 processing by BMP1 are shown.