Parathyroid hormone induces expression and proteolytic processing of Rankl in primary murine osteoblasts
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Parathyroid hormone induces expression and proteolytic processing of Rankl in primary murine osteoblasts. / Heckt, Timo; Keller, Johannes; Peters, Stephanie; Streichert, Thomas; Chalaris, Athena; Rose-John, Stefan; Mell, Blair; Joe, Bina; Amling, Michael; Schinke, Thorsten.
In: BONE, Vol. 92, 11.2016, p. 85-93.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Parathyroid hormone induces expression and proteolytic processing of Rankl in primary murine osteoblasts
AU - Heckt, Timo
AU - Keller, Johannes
AU - Peters, Stephanie
AU - Streichert, Thomas
AU - Chalaris, Athena
AU - Rose-John, Stefan
AU - Mell, Blair
AU - Joe, Bina
AU - Amling, Michael
AU - Schinke, Thorsten
N1 - Copyright © 2016 Elsevier Inc. All rights reserved.
PY - 2016/11
Y1 - 2016/11
N2 - 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.
AB - 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.
U2 - 10.1016/j.bone.2016.08.016
DO - 10.1016/j.bone.2016.08.016
M3 - SCORING: Journal article
C2 - 27554428
VL - 92
SP - 85
EP - 93
JO - BONE
JF - BONE
SN - 8756-3282
ER -