The Soluble Interleukin-6 Receptor Is a Mediator of Hematopoietic and Skeletal Actions of Parathyroid Hormone |
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Authors: | 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 Laurie K McCauley |
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Institution: | 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 |
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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. |
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Keywords: | Bone Bone Marrow Interleukin Myeloid Cell Transforming Growth Factor Beta (TGFbeta) IL-6 Parathyroid Hormone Soluble IL-6 Receptor |
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