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: 10.45). 01/2012; 119(11):2489-99. DOI: 10.1182/blood-2011-06-360933
Source: PubMed


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.

Full-text preview

Available from:
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adult stem cell therapies are increasingly prevalent for the treatment of damaged or diseased tissues, but most of the improvements observed to date are attributed to the ability of stem cells to produce paracrine factors that have a trophic effect on existing tissue cells, improving their functional capacity. It is now clear that this ability to produce trophic factors is a normal and necessary function for some stem cell populations. In vivo adult stem cells are thought to self-renew due to local signals from the microenvironment where they live, the niche. Several niches have now been identified which harbor multiple stem cell populations. In three of these niches - the Drosophila testis, the bulge of the mammalian hair follicle, and the mammalian bone marrow - one type of stem cell has been found to produce factors that contribute to the maintenance of a second stem cell population in the shared niche. In this review, I will examine the architecture of these three niches and discuss the molecular signals involved. Together, these examples establish a new paradigm for stem cell behavior, that stem cells can promote the maintenance of other stem cells.
    Full-text · Article · Dec 2013 · Frontiers in Genetics
  • Source
    • "Osteoblasts and osteocytes express several G-protein coupled receptor (GPCR) and signaling trough these receptor s has been shown to control the niche. Interestingly constitutive activation of the PTH/PTHrP receptor in osteoblasts increased the numbers of HSCs [39] whereas its expression in osteocytes does not [44], suggesting that cells early in the osteoblast lineage are critical for maintaining an intact HSC niche. To examine the role of osteocytes and GPCR signaling in regulation of hematopoiesis we recently generated mice lacking Gsα in osteocytes (Ocy-GsαKO). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The last decade has seen an exponential increase in our understanding of osteocytes function and biology. These cells, once considered inert by-standers trapped into the mineralized bone, has now risen to be key regulators of skeletal metabolism, mineral homeostasis, and hematopoiesis. As tools and techniques to study osteocytes improved and expanded, it has become evident that there is more to these cells than initially thought. Osteocytes are now recognized not only as the key responders to mechanical forces but also as orchestrators of bone remodeling and mineral homeostasis. These cells are the primary source of several important proteins, such as sclerostin and fibroblast growth factor 23, that are currently target as novel therapies for bone loss (as the case for antisclerostin antibodies) or phosphate disorders. Better understanding of the intricate cellular and molecular mechanisms that govern osteocyte biology will open new avenue of research and ultimately indentify novel therapeutics to treat bone and mineral disorders. This review summarizes novel findings and discusses future avenues of research.
    Full-text · Article · Dec 2013
  • Source
    • "Again, HSC number was decreased by conditionally depleting osteoblasts in transgenic mice [28]. However, an expansion in the osteoblast number requires other factors to mediate a proportionate increase in the HSC pool [29]. Some of these factors can be expressed by osteoblasts in vitro, including several cytokines, chemokines, and adhesion molecules, such as CXCL12, angiopoietin-1, stem cell factor (SCF), and thrombopoietin, to maintain HSCs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Leukemia poses a serious challenge to current therapeutic strategies. This has been attributed to leukemia stem cells (LSCs), which occupy endosteal and sinusoidal niches in the bone marrow similar to those of hematopoietic stem cells (HSCs). The signals from these niches provide a viable setting for the maintenance, survival, and fate specifications of these stem cells. Advancements in genetic engineering and microscopy have enabled us to critically deconstruct and analyze the anatomic and functional characteristics of these niches to reveal a wealth of new knowledge in HSC biology, which is quite ahead of LSC biology. In this paper, we examine the present understanding of the regulatory mechanisms governing HSC niches, with the goals of providing a framework for understanding the mechanisms of LSC regulation and suggesting future strategies for their elimination.
    Full-text · Article · Jan 2013 · Advances in Hematology
Show more