Universität zu Köln

Heckt, Timo, Keller, Johannes, Peters, Stephanie, Streichert, Thomas, Chalaris, Athena, Rose-John, Stefan ORCID: 0000-0002-7519-3279, Mell, Blair, Joe, Bina, Amling, Michael and Schinke, Thorsten (2016). Parathyroid hormone induces expression and proteolytic processing of Rankl in primary murine osteoblasts. Bone, 92. S. 85 - 94. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1873-2763

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Abstract

Rankl, the major pro-osteoclastogenic cytokine, is synthesized as a transmembrane protein that can be cleaved by specific endopeptidases to release a soluble form (sRankl). We have previously reported that interleukin-33 (IL-33) induces expression of Tnfsf11, the Rankl-encoding gene, in primary osteoblasts, but we failed to detect sRankl in the medium. Since we also found that PTH treatment caused sRankl release in a similar experimental setting, we directly compared the influence of the two molecules. Here we show that treatment of primary murine osteoblasts with PTH causes sRankl release into the medium, whereas IL-33 only induces Tnfsf11 expression. This difference was not explainable by alternative splicing or by PTH-specific induction of endopeptidases previously shown to facilitate Rankl processing. Since sRankl release after PTH administration was blocked in the presence a broad-spectrum matrix metalloprotease inhibitor, we applied genome-wide expression analyses to identify transcriptional targets of PTH in osteoblasts. We thereby confirmed some of the effects of PTH established in other systems, but additionally identified few PTH-induced genes encoding metalloproteases. By comparing expression of these genes following administration of IL-33, PTH and various other Tnfsf11-inducing molecules, we observed that PTH was the only molecule simultaneously inducing sRankl release and Adamts1 expression. The functional relevance of the putative influence of PTH on Rankl processing was further confirmed in vivo, as we found that daily injection of PTH into wildtype mice did not only increase bone formation, but also osteoclastogenesis and sRankl concentrations in the serum. Taken together, our findings demonstrate that transcriptional effects on Tnfsf11 expression do not generally trigger sRankl release and that PTH has a unique activity to promote the proteolytic processing of Rankl. (C) 2016 Elsevier Inc. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Heckt, Timo UNSPECIFIED UNSPECIFIED UNSPECIFIED Keller, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Peters, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Streichert, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Chalaris, Athena UNSPECIFIED UNSPECIFIED UNSPECIFIED Rose-John, Stefan UNSPECIFIED orcid.org/0000-0002-7519-3279 UNSPECIFIED Mell, Blair UNSPECIFIED UNSPECIFIED UNSPECIFIED Joe, Bina UNSPECIFIED UNSPECIFIED UNSPECIFIED Amling, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Schinke, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-257647
DOI:	10.1016/j.bone.2016.08.016
Journal or Publication Title:	Bone
Volume:	92
Page Range:	S. 85 - 94
Date:	2016
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1873-2763
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language KAPPA-B LIGAND; NECROSIS-FACTOR-ALPHA; OSTEOCLAST DIFFERENTIATION FACTOR; RECEPTOR ACTIVATOR; METALLOPROTEINASE-DISINTEGRIN; TRANSGENIC MICE; BONE-FORMATION; CELLS; ADAMTS-1; OSTEOPROTEGERIN Multiple languages Endocrinology & Metabolism Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25764