Adult hematopoietic stem cells (HSC) continuously replenish the blood with immune and blood cells with a
finite life span, from the bone marrow (BM) reservoir of immature and maturing leukocytes. Regulation of HSC migration
and development is essential for their function and blood cell production. These diverse and multiple states require a tight
regulation to efficiently address host defense and repair requirements. Numerous recent studies disclose a central role for
bone related cells in regulation of HSC and hematopoiesis. During ontogeny HSC home and seed the fetal BM in the last
gestation period when the bone is already ossified. Ossification involves bone forming osteoblast- and bone degrading
osteoclast activity and is considered essential for the formation of BM cavities and hematopoiesis. This synchronized
association implies the need for active bone cells and bone turnover for HSC regulation. Osteoblastic cells and SDF-
1+/nestin+ reticular adventitial and CAR cells are crucial for regulation of HSC lodgment, self-renewal and function. Bone
resorbing osteoclasts regulate bone turnover and progenitor cell detachment and release from the BM. Sympathetic signals
from the nervous system activated by circadian rhythms or stress conditions control both bone turnover and HSC
migration and development. In this review we discuss pathways and mechanisms involved in this orchestrated regulatory
network. A special focus is made on the pivotal role of the SDF-1/CXCR4 axis as a determinant of HSC fate.
Inflammation, DNA damage, cytokine mobilization, microgravity and aging are discussed as specific physiologic and
pathologic events entailing dysregulation of the tightly balanced Bone-Brain-Blood triad.