title: Effects of intermittent parathyroid hormone treatment on osteoprogenitor cells in postmenopausal women.
abstract: Intermittent parathyroid hormone (PTH) 1-34 treatment stimulates bone formation, but the molecular mechanisms mediating this effect have not been previously studied in humans. Thus, we used magnetic activated cell sorting to isolate hematopoietic lineage negative (lin-)/alkaline phosphatase positive (AP+) osteoprogenitor cells from bone marrow of 20 postmenopausal women treated with PTH (1-34) for 14 days and 19 control subjects. Serum PINP and CTX increased in PTH-treated subjects (by 97% and 30%, respectively, P<0.001). Bone marrow lin-/AP+ cells from PTH-treated subjects showed an increase in the RANKL/OPG mRNA ratio (by 7.5-fold, P=0.011) and in the mRNAs for c-fos (a known PTH-responsive gene, by 42%, P=0.035) and VEGF-C (by 57%, P=0.046). Gene Set Enrichment Analysis (GSEA, testing for changes in pre-specified pathways) demonstrated that PTH had no effect on osteoblast proliferation, apoptosis, or differentiation markers. However, PTH treatment resulted in a significant decrease (GSEA P-value, 0.005) in a panel of BMP target genes in the lin-/AP+ cells. Our findings thus identify several future directions for studying mechanisms of PTH action in humans. First, given the increasing evidence that PTH induces angiogenesis, the role of increased VEGF-C production by bone marrow osteoprogenitor cells in mediating this effect and the anabolic response to PTH warrants further study. Second, while the observed inhibition of BMP target gene expression by PTH is not consistent with the anabolic effects of PTH on bone and requires further validation, these data do generate the hypothesis that an inhibition of BMP signaling by PTH may, over time, limit the availability of mature osteoblasts on bone surfaces and thereby contribute to the observed waning of the anabolic response to PTH.
authors: Endocrine Research Unit, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors: Matthew T
authors: MT
authors: Drake
authors: Bhuma
authors: B
authors: Srinivasan
authors: Ulrike I
authors: UI
authors: Mödder
authors: Alvin C
authors: AC
authors: Ng
authors: Anita H
authors: AH
authors: Undale
authors: Matthew M
authors: MM
authors: Roforth
authors: James M
authors: JM
authors: Peterson
authors: Louise K
authors: LK
authors: McCready
authors: B Lawrence
authors: BL
authors: Riggs
authors: Sundeep
authors: S
authors: Khosla
references: J Comput Biol. 2005 Oct;12(8):1047-64
references: 16241897
references: Bone. 2009 May;44(5):1010-4
references: 19223260
references: Annu Int Conf IEEE Eng Med Biol Soc. 2009;2009:1004-7
references: 19964493
references: J Clin Invest. 2003 Apr;111(8):1221-30
references: 12697741
references: Cell Metab. 2006 Aug;4(2):111-21
references: 16890539
references: Endocrinology. 1999 Aug;140(8):3552-61
references: 10433211
references: Endocrinology. 1990 Dec;127(6):3111-6
references: 2174346
references: Endocrinology. 2005 Nov;146(11):4577-83
references: 16081646
references: Bone. 2006 Jul;39(1):189-98
references: 16516570
references: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references: 16199517
references: J Biol Chem. 2007 Nov 9;282(45):33086-97
references: 17690103
references: J Cell Biochem. 2003 May 1;89(1):180-90
references: 12682918
references: Nucleic Acids Res. 2006 Feb 09;34(3):996-1014
references: 16473852
references: N Engl J Med. 2001 May 10;344(19):1434-41
references: 11346808
references: Biotechniques. 2004 Nov;37(5):854-7
references: 15560142
references: Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
references: 12184808
references: J Bone Miner Res. 2001 Oct;16(10):1846-53
references: 11585349
references: J Bone Miner Res. 2004 Feb;19(2):235-44
references: 14969393
references: Bone. 2009 Dec;45(6):1053-8
references: 19679211
references: Stem Cells. 2007 Nov;25(11):2739-49
references: 17656645
references: Bone. 2010 Jul;47(1):83-92
references: 20362080
references: Endocrinology. 1995 Aug;136(8):3632-8
references: 7628403
references: J Clin Endocrinol Metab. 2009 Oct;94(10):3772-80
references: 19584192
references: Stem Cells Dev. 2007 Dec;16(6):953-63
references: 18158854
references: J Bone Miner Res. 2009 Jun;24(6):1110-5
references: 19113926
references: J Clin Endocrinol Metab. 2010 Nov;95(11):5056-62
references: 20631014
references: J Clin Endocrinol Metab. 2006 Aug;91(8):2882-7
references: 16684825
references: J Bone Miner Res. 2005 Dec;20(12):2233-44
references: 16294276
references: J Bone Miner Res. 2008 May;23(5):705-14
references: 18086006
references: Lancet. 1997 Aug 23;350(9077):550-5
references: 9284777
references: J Biol Chem. 2003 May 30;278(22):19723-31
references: 12644456
references: J Bone Miner Res. 2007 Apr;22(4):495-502
references: 17227219
references: J Mol Histol. 2007 Aug;38(4):261-9
references: 17549589
references: Bone. 2005 Aug;37(2):148-58
references: 15946907
references: J Clin Invest. 2008 Feb;118(2):421-8
references: 18246192
references: Biochem Biophys Res Commun. 2004 Jan 23;313(4):856-62
references: 14706621
references: Bone. 2007 Jun;40(6):1434-46
references: 17517365
references: J Bone Miner Res. 2010 Nov;25(11):2427-37
references: 20533302
references: J Bone Miner Res. 2010 Feb;25(2):178-89
references: 19594304
references: J Clin Endocrinol Metab. 2009 Jul;94(7):2495-501
references: 19401368