Osteoblastic expansion induced by parathyroid hormone receptor signaling in murine osteocytes is not sufficient to increase hematopoietic stem cells

Department of Medicine, Division of Endocrinology, and J. P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, NY 14642, USA.
Blood (Impact Factor: 10.43). 01/2012; 119(11):2489-99. DOI: 10.1182/blood-2011-06-360933
Source: PubMed

ABSTRACT Microenvironmental expansion of hematopoietic stem cells (HSCs) is induced by treatment with parathyroid hormone (PTH) or activation of the PTH receptor (PTH1R) in osteoblastic cells; however, the osteoblastic subset mediating this action of PTH is unknown. Osteocytes are terminally differentiated osteoblasts embedded in mineralized bone matrix but are connected with the BM. Activation of PTH1R in osteocytes increases osteoblastic number and bone mass. To establish whether osteocyte-mediated PTH1R signaling expands HSCs, we studied mice expressing a constitutively active PTH1R in osteocytes (TG mice). Osteoblasts, osteoclasts, and trabecular bone were increased in TG mice without changes in BM phenotypic HSCs or HSC function. TG mice had progressively increased trabecular bone but decreased HSC function. In severely affected TG mice, phenotypic HSCs were decreased in the BM but increased in the spleen. TG osteocytes had no increase in signals associated with microenvironmental HSC support, and the spindle-shaped osteoblastic cells that increased with PTH treatment were not present in TG bones. These findings demonstrate that activation of PTH1R signaling in osteocytes does not expand BM HSCs, which are instead decreased in TG mice. Therefore, osteocytes do not mediate the HSC expansion induced by PTH1R signaling. Further, osteoblastic expansion is not sufficient to increase HSCs.

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    • "Mendez-Ferrer et al. found that G-CSF caused downregulation of HSC self-renewal factors specifically in nestinGFPpositive cells, as well as a decrease in the nestinGFP-positive cell proliferation levels (Mendez-Ferrer et al., 2010). Parathormone treatment, which was previously shown to expand HSC numbers (presumably by increasing the size of the niche), led to a doubling in the number of nestinGFP-positive cells, while activation of parathormone signaling in only differentiated osteoblasts had no effect on HSC numbers (Mendez-Ferrer et al., 2010; Calvi et al., 2012). Finally, cotransplantation of MsSCs along with HSCs during transplantation greatly improved HSC engraftment and self-renewal (Masuda et al., 2009; Ahn et al., 2010). "
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