Publications by authors named "Jonathan M Weber"

5 Publications

  • Page 1 of 1

Osteoblastic N-cadherin is not required for microenvironmental support and regulation of hematopoietic stem and progenitor cells.

Blood 2012 Jul 17;120(2):303-13. Epub 2012 May 17.

Endocrine Division, Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Ave, Rochester, NY 14642, USA.

Hematopoietic stem cell (HSC) regulation is highly dependent on interactions with the marrow microenvironment. Controversy exists on N-cadherin's role in support of HSCs. Specifically, it is unknown whether microenvironmental N-cadherin is required for normal marrow microarchitecture and for hematopoiesis. To determine whether osteoblastic N-cadherin is required for HSC regulation, we used a genetic murine model in which deletion of Cdh2, the gene encoding N-cadherin, has been targeted to cells of the osteoblastic lineage. Targeted deletion of N-cadherin resulted in an age-dependent bone phenotype, ultimately characterized by decreased mineralized bone, but no difference in steady-state HSC numbers or function at any time tested, and normal recovery from myeloablative injury. Intermittent parathyroid hormone (PTH) treatment is well established as anabolic to bone and to increase marrow HSCs through microenvironmental interactions. Lack of osteoblastic N-cadherin did not block the bone anabolic or the HSC effects of PTH treatment. This report demonstrates that osteoblastic N-cadherin is not required for regulation of steady-state hematopoiesis, HSC response to myeloablation, or for rapid expansion of HSCs through intermittent treatment with PTH.
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http://dx.doi.org/10.1182/blood-2011-09-377853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398755PMC
July 2012

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

Blood 2012 Mar 18;119(11):2489-99. Epub 2012 Jan 18.

Department of Medicine, Division of Endocrinology, and J. P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, NY 14642, USA.

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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http://dx.doi.org/10.1182/blood-2011-06-360933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311272PMC
March 2012

In vivo prostaglandin E2 treatment alters the bone marrow microenvironment and preferentially expands short-term hematopoietic stem cells.

Blood 2009 Nov 2;114(19):4054-63. Epub 2009 Sep 2.

Endocrine Division, University of Rochester School of Medicine, Rochester, NY 14642, USA.

Microenvironmental signals can determine hematopoietic stem cell (HSC) fate choices both directly and through stimulation of niche cells. In the bone marrow, prostaglandin E(2) (PGE(2)) is known to affect both osteoblasts and osteoclasts, whereas in vitro it expands HSCs and affects differentiation of hematopoietic progenitors. We hypothesized that in vivo PGE(2) treatment could expand HSCs through effects on both HSCs and their microenvironment. PGE(2)-treated mice had significantly decreased number of bone trabeculae, suggesting disruption of their microarchitecture. In addition, in vivo PGE(2) increased lineage(-) Sca-1(+) c-kit(+) bone marrow cells without inhibiting their differentiation. However, detailed immunophenotyping demonstrated a PGE(2)-dependent increase in short-term HSCs/multipotent progenitors (ST-HSCs/MPPs) only. Bone marrow cells transplanted from PGE(2) versus vehicle-treated donors had superior lymphomyeloid reconstitution, which ceased by 16 weeks, also suggesting that ST-HSCs were preferentially expanded. This was confirmed by serial transplantation studies. Thus in vivo PGE(2) treatment, probably through a combination of direct and microenvironmental actions, preferentially expands ST-HSCs in the absence of marrow injury, with no negative impact on hematopoietic progenitors or long-term HSCs. These novel effects of PGE(2) could be exploited clinically to increase donor ST-HSCs, which are highly proliferative and could accelerate hematopoietic recovery after stem cell transplantation.
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http://dx.doi.org/10.1182/blood-2009-03-205823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774547PMC
November 2009

Notch signaling and the bone marrow hematopoietic stem cell niche.

Bone 2010 Feb 11;46(2):281-5. Epub 2009 Aug 11.

Endocrine Division, Wilmot Cancer Center, Department of Medicine and Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, NY 14642, USA.

Recently there has been increased interest in the regulatory interactions between osteoblasts and cells in the surrounding bone marrow microenvironment. The proximity of hematopoietic stem cells (HSCs) with osteoblastic cells first suggested regulatory interactions, and recent data have highlighted the role of osteoblastic cells in providing a HSC niche. Reports have indicated that direct contact is necessary to mediate the osteoblastic effects and that these effects could be mediated through Notch activation. Notch signaling is important throughout development and also appears to play a critical role in cellular maturation and differentiation of osteoblastic cells and hematopoietic cells as disregulation can lead to bone loss and leukemias, respectively. In this review we discuss the current understanding of Notch signaling and how it functions in hematopoiesis, osteoblastic cells, and the interactions between HSC and their osteoblastic niche.
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http://dx.doi.org/10.1016/j.bone.2009.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073451PMC
February 2010

Parathyroid hormone stimulates expression of the Notch ligand Jagged1 in osteoblastic cells.

Bone 2006 Sep 2;39(3):485-93. Epub 2006 May 2.

Endocrine Division, Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Avenue Box 693 Rochester, NY 14642, USA.

We previously demonstrated that activation of the Parathyroid Hormone Receptor (PTH1R) in osteoblastic cells increases the Notch ligand Jagged1 and expands hematopoietic stem cells (HSC) through Notch signaling. However, regulation of Jagged1 by PTH in osteoblasts is poorly understood. The present study demonstrates that PTH treatment increases Jagged1 levels in a subpopulation of osteoblastic cells in vivo and in UMR106 osteoblastic cells in vitro. Since PTH(1-34) activates both Adenylate Cyclase/Protein Kinase A (AC/PKA) and Protein Kinase C (PKC) downstream of the PTH1R in osteoblastic cells, we independently determined the effect of either pathway on Jagged1. Activation of AC with Forskolin or PKA with PTH(1-31) or cell-permeable cAMP analogues increased osteoblastic Jagged1. This PTH-dependent Jagged1 increase was blocked by H89 and PKI, specific PKA inhibitors. In contrast, PKC activation with phorbol ester (PMA) or PTH(13-34) did not stimulate Jagged1 expression, and PTH-dependent Jagged1 stimulation was not blocked by Gö6976, a conventional PKC inhibitor. Therefore, PTH treatment stimulates osteoblastic Jagged1 mainly through the AC/PKA signaling pathway downstream of the PTH1R. Since Jagged1/Notch signaling has been implicated not only in stromal-HSC interactions but also in osteoblastic differentiation, Jagged1 may play a critical role in mediating the PTH-dependent expansion of HSC, as well as the anabolic effect of PTH in bone.
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http://dx.doi.org/10.1016/j.bone.2006.03.002DOI Listing
September 2006