Bone Is a Major Target of PTH/PTHrP Receptor Signaling in Regulation of Fetal Blood Calcium Homeostasis

Abstract

The blood calcium concentration during fetal life is tightly regulated within a narrow range by highly interactive homeostatic mechanisms that include transport of calcium across the placenta and fluxes in and out of bone; the mechanisms of this regulation are poorly understood. Our findings that endochondral bone-specific PTH/PTHrP receptor (PPR) knockout (KO) mice showed significant reduction of fetal blood calcium concentration compared with that of control littermates at embryonic day 18.5 led us to focus on bone as a possibly major determinant of fetal calcium homeostasis. We found that the fetal calcium concentration of Runx2 KO mice was significantly higher than that of control littermates, suggesting that calcium flux into bone had a considerable influence on the circulating calcium concentration. Moreover, Runx2:PTH double mutant fetuses showed calcium levels similar to those of Runx2 KO mice, suggesting that part of the fetal hypocalcemia in PTH KO mice was caused by the increment of the mineralized bone mass allowed by the formation of osteoblasts. Finally, Rank:PTH double mutant mice had a blood calcium concentration even lower than that of the either Rank KO or PTH KO mice alone at embryonic day 18.5. These observations in our genetic models suggest that PTH/PTHrP receptor signaling in bones has a significant role of the regulation of fetal blood calcium concentration and that both placental transport and osteoclast activation contribute to PTH's hypercalcemic action. They also show that PTH-independent deposition of calcium in bone is the major controller of fetal blood calcium level.

In Vivo Rescue of the Hematopoietic Niche By Pluripotent Stem Cell Complementation of Defective Osteoblast Compartments

“…Runx2 –/– mice and Osx1‐Cre mice have been described. ROSA26 eGFP‐DTA mice were purchased from the Jackson Laboratory (Bar Harbor, ME, https://www.jax.org/jax-mice-and-services).…”

α1B‐Adrenoceptor signalling regulates bone formation through the up‐regulation of CCAAT/enhancer‐binding protein δ expression in osteoblasts

“…Measurements were made within an area of 0.8 mm 2 (1.0 × 0.8 mm), with its closest and furthest edges being 2.0 and 3.0 mm distal to the growth plate of the proximal ends of the tibia respectively. Osteoclast number per bone surface (Oc.N/BS) and osteoclast surface per bone surface (Oc.S/BS) were evaluated by scoring TRAP‐positive multinucleated cells attached to the bone surface (Hirai et al, ).…”

Doxercalciferol Alleviates Bone Deteriorations and Cartilage Degeneration in Aging Mice

“…DOX as a forcefully modulator of PTH has been used for the treatment of SHPT in CKD patients [8,17]. The function of kidney and bone is linked by PTH in blood calcium homeostasis [18]. PTH directly stimulates Ca 2+ mobilization into the systemic circulation from bone or increases distal tubular Ca 2+ reabsorption [18].…”

“…The function of kidney and bone is linked by PTH in blood calcium homeostasis [18]. PTH directly stimulates Ca 2+ mobilization into the systemic circulation from bone or increases distal tubular Ca 2+ reabsorption [18]. In addition, reduction of blood Ca 2+ levels can also accelerate PTH secretion from the parathyroid gland [19].…”