Erythropoietin couples hematopoiesis with bone formation.
BACKGROUND
It is well established that bleeding activates the hematopoietic system to regenerate the loss of mature blood elements. We have shown that hematopoietic stem cells (HSCs) isolated from animals challenged with an acute bleed regulate osteoblast differentiation from marrow stromal cells. This suggests that HSCs participate in bone formation where the molecular basis for this activity is the production of BMP2 and BMP6 by HSCs. Yet, what stimulates HSCs to produce BMPs is unclear.


RESULTS
In this study, we demonstrate that erythropoietin (Epo) activates Jak-Stat signaling pathways in HSCs which leads to the production of BMPs. Critically, Epo also directly activates mesenchymal cells to form osteoblasts in vitro, which in vivo leads to bone formation. Importantly, Epo first activates osteoclastogenesis which is later followed by osteoblastogenesis that is induced by either Epo directly or the expression of BMPs by HSCs to form bone.


CONCLUSIONS
These data for the first time demonstrate that Epo regulates the formation of bone by both direct and indirect pathways, and further demonstrates the exquisite coupling between hematopoiesis and osteopoiesis in the marrow.
Shiozawa
Yusuke
Y
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
Jung
Younghun
Y
Ziegler
Anne M
AM
Pedersen
Elisabeth A
EA
Wang
Jianhua
J
Wang
Zhuo
Z
Song
Junhui
J
Wang
Jingcheng
J
Lee
Clara H
CH
Sud
Sudha
S
Pienta
Kenneth J
KJ
Krebsbach
Paul H
PH
Taichman
Russell S
RS
D000818:Animals; D000831:Animals, Newborn; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism* / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D017467:Receptors, Erythropoietin / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D017467:Receptors, Erythropoietin; D004921:Erythropoietin