Effects of intermittent parathyroid hormone treatment on osteoprogenitor cells in postmenopausal women

Matthew M Drake, Bhuma Srinivasan, Ulrike I. Mödder, Alvin C. Ng, Anita H. Undale, Matthew M. Roforth, James M. Peterson, Louise K. McCready, B. Lawrence Riggs, Sundeep Khosla

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)349-355
Number of pages7
JournalBone
Volume49
Issue number3
DOIs
StatePublished - Sep 2011

Fingerprint

Parathyroid Hormone
Therapeutics
Vascular Endothelial Growth Factor C
Osteoblasts
Bone Marrow Cells
Genes
Anabolic Agents
Bone and Bones
Messenger RNA
Differentiation Antigens
Osteogenesis
Alkaline Phosphatase
Bone Marrow

Keywords

  • Anabolic
  • Osteoporosis
  • Postmenopausal women
  • PTH

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

Cite this

Effects of intermittent parathyroid hormone treatment on osteoprogenitor cells in postmenopausal women. / Drake, Matthew M; Srinivasan, Bhuma; Mödder, Ulrike I.; Ng, Alvin C.; Undale, Anita H.; Roforth, Matthew M.; Peterson, James M.; McCready, Louise K.; Riggs, B. Lawrence; Khosla, Sundeep.

In: Bone, Vol. 49, No. 3, 09.2011, p. 349-355.

Research output: Contribution to journalArticle

Drake, MM, Srinivasan, B, Mödder, UI, Ng, AC, Undale, AH, Roforth, MM, Peterson, JM, McCready, LK, Riggs, BL & Khosla, S 2011, 'Effects of intermittent parathyroid hormone treatment on osteoprogenitor cells in postmenopausal women', Bone, vol. 49, no. 3, pp. 349-355. https://doi.org/10.1016/j.bone.2011.05.003
Drake, Matthew M ; Srinivasan, Bhuma ; Mödder, Ulrike I. ; Ng, Alvin C. ; Undale, Anita H. ; Roforth, Matthew M. ; Peterson, James M. ; McCready, Louise K. ; Riggs, B. Lawrence ; Khosla, Sundeep. / Effects of intermittent parathyroid hormone treatment on osteoprogenitor cells in postmenopausal women. In: Bone. 2011 ; Vol. 49, No. 3. pp. 349-355.
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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.",
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