Parathyroid hormone (PTH) and hematopoiesis: New support for some old observations

Abstract

Forty-seven years ago, the parathyroid hormone (PTH) in one injection of Lilly's old bovine parathyroid extract, PTE, was found to greatly increase the 30-day survival of heavily X-irradiated rats when given from 18 h before to as long as 3 h after irradiation but no later. This was the first indication that PTH might stimulate hematopoiesis. Recent studies have confirmed the relation between PTH and hematopoiesis by showing that hPTH-(1-34)OH increases the size of the hematopoietic stem cell pool in mice. The peptide operates through a cyclic AMP-mediated burst of Jagged 1 production in osteoblastic cells lining the stem cells' niches on trabecular bone surfaces. The osteoblastic cells' Jagged 1 increases the hematopoietic stem cell pool by activating Notch receptors on attached stem cells. PTH-triggered cyclic AMP signals also directly stimulate the proliferation of the hematopoietic stem cells. However, the single PTH injection in the early experiments using PTE probably increased the survival of irradiated rats mainly by preventing the damaged hematopoietic progenitors from irreversibly initiating self-destructive apoptogenesis during the first 5 h after irradiation. It has also been shown that several daily injections of hPTH-(1-34)OH enable lethally irradiated mice to survive by stimulating the growth of transplanted normal bone marrow cells. If the osteogenic PTHs currently entering or on the verge of entering the market for treating osteoporosis can also drive hematopoiesis in humans as well as rodents, they could be potent tools for reducing the damage inflicted on bone marrow by cytotoxic cancer chemotherapeutic drugs and ionizing radiation.

Parathyroid Hormone Administration Improves Bone Marrow Microenvironment and Partially Rescues Haematopoietic Defects in Bmi1-Null Mice

“…It was reported that PTH not only exerts bone anabolic action by stimulating osteoblastic bone formation, but also promotes haematopoiesis by improving the bone marrow microenvironment [5], [16]–[18]. In the present study, we have investigated whether PTH administration rescues the haematopoietic defects caused by Bmi1 deficiency though improving the haematopoietic microenvironment.…”

“…On the other hand, PTH mediated activation of osteoblasts resulted in a significant expansion of the HSC pool and led to the realization that targeting cells of the osteoblastic lineage is a potential therapeutic approach to enhance stem cell-based therapies [5], [16]–[18]. Base on that PTH1-34 administration increased osteoblastic bone formation in Bmi1 -deficient mice, we assessed whether PTH1-34 administration could also rescue defects in haematopoiesis caused by Bmi1 deficiency.…”

“…Our previous study demonstrated that PTH1-34 administration significantly increased cortical and trabecular bone mass with augmented osteoblast number and activity [15]. Furthermore, available evidence also suggests that PTH stimulates haematopoiesis [5], [16]–[18]. Osteoblasts in transgenic mice expressing a constitutively active form of PTHR only in the osteoblast lineage support accumulation of twice more HSCs than normal [5].…”

Parathyroid Hormone (1–34) Transiently Protects Against Radiation-Induced Bone Fragility

“…PTH is known to promote hematopoietic progenitor cell survival if delivered within a few hours of radiation exposure [26, 27]. Additionally, PTH has been shown to increase osteoclast progenitor populations in vivo and potentiate osteoclastic activity, although this has only been demonstrated following shorter durations of PTH dosing [28].…”

Different Radiosensitive Megakaryocytic Progenitor Cells Exist in Steady-State Human Peripheral Blood

“…In addition, a single injection of PTH increased survival of irradiated rats when given 3 h after irradiation (60). The PTH molecule is believed to function in this model by preventing damaged hematopoietic progenitors from irreversibly initiating apoptosis during the first few hours after irradiation (61). In studies in both mice and NHPs, PTH also increased platelet counts and overall survival when given at later times postexposure (A. Bartholomew).…”