Abstract
Parathyroid hormone (PTH) stimulates hematopoietic cells through mechanisms of action that remain elusive. Interleukin-6 (IL-6) is upregulated by PTH and stimulates hematopoiesis. The purpose of this investigation was to identify actions of PTH and IL-6 in hematopoietic cell expansion. Bone marrow cultures from C57B6 mice were treated with fms-like tyrosine kinase-3 ligand (Flt-3L), PTH, Flt-3L plus PTH, or vehicle control. Flt-3L alone increased adherent and non-adherent cells. PTH did not directly impact hematopoietic or osteoclastic cells but acted in concert with Flt-3L to further increase cell numbers. Flt-3L alone stimulated proliferation, while PTH combined with Flt-3L decreased apoptosis. Flt-3L increased blasts early in culture, and later increased CD45+ and CD11b+ cells. In parallel experiments, IL-6 acted additively with Flt-3L to increase cell numbers and IL-6-deficient bone marrow cultures (compared to wildtype controls) but failed to amplify in response to Flt-3L and PTH, suggesting that IL-6 mediated the PTH effect. In vivo, PTH increased Lin- Sca-1+c-Kit+ (LSK) hematopoietic progenitor cells after PTH treatment in wildtype mice, but failed to increase LSKs in IL-6-deficient mice. In conclusion, PTH acts with Flt-3L to maintain hematopoietic cells by limiting apoptosis. IL-6 is a critical mediator of bone marrow cell expansion and is responsible for PTH actions in hematopoietic cell expansion.
Highlights
Parathyroid hormone (PTH) and parathyroid hormone related protein are pleiotropic factors that operate via endocrine, paracrine, autocrine and intracrine modes of action
When PTH was added in conjunction with fms-like tyrosine kinase3 ligand (Flt-3L), there was an additive increase in non-adherent cell numbers compared to Flt-3L alone at day 8, suggesting that PTH selectively targeted the Flt-3L responsive population
The present study revealed that PTH increased cells of the hematopoietic lineage by indirectly decreasing hematopoietic cell apoptosis
Summary
Parathyroid hormone (PTH) and parathyroid hormone related protein are pleiotropic factors that operate via endocrine, paracrine, autocrine and intracrine modes of action. Despite extensive research on PTH skeletal actions, the mechanisms for the hematopoietic impact are still elusive Both direct and indirect actions of PTH on cells of the hematopoietic lineage have been proposed. PTH has long been known to activate osteoclasts, cells of hematopoietic origin formed by the differentiation and fusion of mononuclear monocytemacrophage lineage precursors that are responsible for bone resorption. This activation is widely accepted to be indirect via an upregulation of RANK-L in cells of the osteoblast lineage [7], reports exist of PTH receptors in osteoclasts as well [8,9]. Many unanswered questions persist regarding the impact of PTH on the variety of cells occupying the bone marrow microenvironment
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