The Soluble Interleukin-6 Receptor Is a Mediator of Hematopoietic and Skeletal Actions of Parathyroid Hormone*
- Sun Wook Cho‡,
- Flavia Q. Pirih‡,
- Amy J. Koh‡,
- Megan Michalski‡,
- Matthew R. Eber‡,
- Kathryn Ritchie‡,
- Benjamin Sinder§,
- Seojin Oh‡,
- Saja A. Al-Dujaili‡,
- JoonHo Lee‡,
- Ken Kozloff§,
- Theodora Danciu‡,
- Thomas J. Wronski¶ and
- Laurie K. McCauley‡‖,1
- From the ‡Department of Periodontics and Oral Medicine, School of Dentistry and
- the Departments of ‖Pathology and
- §Orthopaedic Surgery, Medical School, University of Michigan, Ann Arbor, Michigan 48109-1078 and
- the ¶Department of Physiological Sciences, University of Florida, Gainesville, Florida 32611
- ↵1 To whom correspondence should be addressed: University of Michigan, School of Dentistry, 1011 N. University Ave., Ann Arbor, MI 48109-1078. Tel.: 734-647-3206; E-mail: mccauley{at}umich.edu.
Abstract
Both PTH and IL-6 signaling play pivotal roles in hematopoiesis and skeletal biology, but their interdependence is unclear. The purpose of this study was to evaluate the effect of IL-6 and soluble IL-6 receptor (sIL-6R) on hematopoietic and skeletal actions of PTH. In the bone microenvironment, PTH stimulated sIL-6R protein levels in primary osteoblast cultures in vitro and bone marrow in vivo in both IL-6+/+ and IL-6−/− mice. PTH-mediated hematopoietic cell expansion was attenuated in IL-6−/− compared with IL-6+/+ bone marrow, whereas sIL-6R treatment amplified PTH actions in IL-6−/− earlier than IL-6+/+ marrow cultures. Blocking sIL-6R signaling with sgp130 (soluble glycoprotein 130 receptor) inhibited PTH-dependent hematopoietic cell expansion in IL-6−/− marrow. In the skeletal system, although intermittent PTH administration to IL-6+/+ and IL-6−/− mice resulted in similar anabolic actions, blocking sIL-6R significantly attenuated PTH anabolic actions. sIL-6R showed no direct effects on osteoblast proliferation or differentiation in vitro; however, it up-regulated myeloid cell expansion and production of the mesenchymal stem cell recruiting agent, TGF-β1 in the bone marrow microenvironment. Collectively, sIL-6R demonstrated orphan function and mediated PTH anabolic actions in bone in association with support of myeloid lineage cells in the hematopoietic system.
- Bone
- Bone Marrow
- Interleukin
- Myeloid Cell
- Transforming Growth Factor Beta (TGFbeta)
- IL-6
- Parathyroid Hormone
- Soluble IL-6 Receptor
Footnotes
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↵* This work was supported, in whole or in part, by National Institutes of Health Grants DK53904 and PO1 CA093900 (to L. K. M.).
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This article contains supplemental Figs. S1–S6.
- Received June 26, 2012.
- Revision received December 16, 2012.
- © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.
