IL-17 Receptor Signaling in Osteoblasts/Osteocytes Mediates PTH-Induced Bone Loss and Enhances Osteocytic RANKL Production

Jau Yi Li, Mingcan Yu, Abdul Malik Tyagi, Chiara Vaccaro, Emory Hsu, Jonathan Adams, Teresita Bellido, M. Neale Weitzmann, Roberto Pacifici

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Primary hyperparathyroidism (PHPT) is a condition where elevated PTH levels lead to bone loss, in part through increased production of the osteoclastogenic factor IL-17A, by bone marrow (BM) T-helper 17 (Th17) cells, a subset of helper CD4+ T cells. In animals, PHPT is modeled by continuous PTH treatment (cPTH). In mice, an additional critical action of cPTH is the capacity to increase the production of RANKL by osteocytes. However, a definitive link between IL-17A and osteocytic expression of RANKL has not been made. Here we show that cPTH fails to induce cortical and trabecular bone loss and causes less intense bone resorption in conditional knock-out (IL-17RAΔOCY) male and female mice lacking the expression of IL-17A receptor (IL-17RA) in dentin matrix protein 1 (DMP1)-8kb-Cre–expressing cells, which include osteocytes and some osteoblasts. Therefore, direct IL-17RA signaling in osteoblasts/osteocytes is required for cPTH to exert its bone catabolic effects. In addition, in vivo, silencing of IL-17RA signaling in in DMP1-8kb–expressing cells blunts the capacity of cPTH to stimulate osteocytic RANKL production, indicating that cPTH augments osteocytic RANKL expression indirectly, via an IL-17A/IL-17RA–mediated mechanism. Thus, osteocytic production of RANKL and T cell production of IL-17A are both critical for the bone catabolic activity of cPTH.

Original languageEnglish (US)
JournalJournal of Bone and Mineral Research
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Interleukin-17 Receptors
Osteocytes
Interleukin-17
Osteoblasts
Bone and Bones
Primary Hyperparathyroidism
Dentin
Th17 Cells
Bone Resorption
Helper-Inducer T-Lymphocytes
Proteins
Bone Marrow
T-Lymphocytes

Keywords

  • BONE
  • IL-17
  • IL-17R
  • PTH
  • T CELLS
  • TH17 CELLS

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

IL-17 Receptor Signaling in Osteoblasts/Osteocytes Mediates PTH-Induced Bone Loss and Enhances Osteocytic RANKL Production. / Li, Jau Yi; Yu, Mingcan; Tyagi, Abdul Malik; Vaccaro, Chiara; Hsu, Emory; Adams, Jonathan; Bellido, Teresita; Weitzmann, M. Neale; Pacifici, Roberto.

In: Journal of Bone and Mineral Research, 01.01.2018.

Research output: Contribution to journalArticle

Li, Jau Yi ; Yu, Mingcan ; Tyagi, Abdul Malik ; Vaccaro, Chiara ; Hsu, Emory ; Adams, Jonathan ; Bellido, Teresita ; Weitzmann, M. Neale ; Pacifici, Roberto. / IL-17 Receptor Signaling in Osteoblasts/Osteocytes Mediates PTH-Induced Bone Loss and Enhances Osteocytic RANKL Production. In: Journal of Bone and Mineral Research. 2018.
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AU - Li, Jau Yi

AU - Yu, Mingcan

AU - Tyagi, Abdul Malik

AU - Vaccaro, Chiara

AU - Hsu, Emory

AU - Adams, Jonathan

AU - Bellido, Teresita

AU - Weitzmann, M. Neale

AU - Pacifici, Roberto

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N2 - Primary hyperparathyroidism (PHPT) is a condition where elevated PTH levels lead to bone loss, in part through increased production of the osteoclastogenic factor IL-17A, by bone marrow (BM) T-helper 17 (Th17) cells, a subset of helper CD4+ T cells. In animals, PHPT is modeled by continuous PTH treatment (cPTH). In mice, an additional critical action of cPTH is the capacity to increase the production of RANKL by osteocytes. However, a definitive link between IL-17A and osteocytic expression of RANKL has not been made. Here we show that cPTH fails to induce cortical and trabecular bone loss and causes less intense bone resorption in conditional knock-out (IL-17RAΔOCY) male and female mice lacking the expression of IL-17A receptor (IL-17RA) in dentin matrix protein 1 (DMP1)-8kb-Cre–expressing cells, which include osteocytes and some osteoblasts. Therefore, direct IL-17RA signaling in osteoblasts/osteocytes is required for cPTH to exert its bone catabolic effects. In addition, in vivo, silencing of IL-17RA signaling in in DMP1-8kb–expressing cells blunts the capacity of cPTH to stimulate osteocytic RANKL production, indicating that cPTH augments osteocytic RANKL expression indirectly, via an IL-17A/IL-17RA–mediated mechanism. Thus, osteocytic production of RANKL and T cell production of IL-17A are both critical for the bone catabolic activity of cPTH.

AB - Primary hyperparathyroidism (PHPT) is a condition where elevated PTH levels lead to bone loss, in part through increased production of the osteoclastogenic factor IL-17A, by bone marrow (BM) T-helper 17 (Th17) cells, a subset of helper CD4+ T cells. In animals, PHPT is modeled by continuous PTH treatment (cPTH). In mice, an additional critical action of cPTH is the capacity to increase the production of RANKL by osteocytes. However, a definitive link between IL-17A and osteocytic expression of RANKL has not been made. Here we show that cPTH fails to induce cortical and trabecular bone loss and causes less intense bone resorption in conditional knock-out (IL-17RAΔOCY) male and female mice lacking the expression of IL-17A receptor (IL-17RA) in dentin matrix protein 1 (DMP1)-8kb-Cre–expressing cells, which include osteocytes and some osteoblasts. Therefore, direct IL-17RA signaling in osteoblasts/osteocytes is required for cPTH to exert its bone catabolic effects. In addition, in vivo, silencing of IL-17RA signaling in in DMP1-8kb–expressing cells blunts the capacity of cPTH to stimulate osteocytic RANKL production, indicating that cPTH augments osteocytic RANKL expression indirectly, via an IL-17A/IL-17RA–mediated mechanism. Thus, osteocytic production of RANKL and T cell production of IL-17A are both critical for the bone catabolic activity of cPTH.

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