Parathyroid hormone mediates hematopoietic cell expansion through interleukin-6.
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.
University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
Flavia Q
FQ
Pirih
Megan N
MN
Michalski
Sun W
SW
Cho
Amy J
AJ
Koh
Janice E
JE
Berry
Eduardo
E
Ghaname
Pachiyappan
P
Kamarajan
Edith
E
Bonnelye
Charles W
CW
Ross
Yvonne L
YL
Kapila
Pierre
P
Jurdic
Laurie K
LK
McCauley
D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D002448:Cell Adhesion; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects*; D019070:Cell Lineage; D005434:Flow Cytometry; D015850:Interleukin-6 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology; D010281:Parathyroid Hormone / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015850:Interleukin-6; D010281:Parathyroid Hormone