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Priority Research Paper|Volume 13, Issue 24|pp 25607—25642

Parathyroid hormone signaling in mature osteoblasts/osteocytes protects mice from age-related bone loss

Yuhei Uda1, Vaibhav Saini2, Christopher A. Petty1, Majed Alshehri1, Chao Shi1,3, Jordan M. Spatz2,4, Roberto Santos1, Carly M. Newell1, Tim Y. Huang1, Alejandro Kochen1, Ji W. Kim1, Christodoulos K. Constantinou1, Hiroaki Saito5, Kathryn D. Held6, Eric Hesse5, Paola Divieti Pajevic1,2
  • 1Department of Translational Dental Medicine, Goldman School of Dental Medicine, Boston University, Boston, MA 02118, USA
  • 2Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
  • 3Department of Orthopaedics, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, P.R. China
  • 4School of Medicine, University of California San Francisco, San Francisco, CA 94143, USA
  • 5Heisenberg-Group for Molecular Skeletal Biology, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany
  • 6Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
* Equal contribution as co-first authors
Received: September 20, 2021Accepted: November 30, 2021Published: December 30, 2021
https://doi.org/10.18632/aging.203808

Copyright: © 2021 Uda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Aging is accompanied by osteopenia, characterized by reduced bone formation and increased bone resorption. Osteocytes, the terminally differentiated osteoblasts, are regulators of bone homeostasis, and parathyroid hormone (PTH) receptor (PPR) signaling in mature osteoblasts/osteocytes is essential for PTH-driven anabolic and catabolic skeletal responses. However, the role of PPR signaling in those cells during aging has not been investigated. The aim of this study was to analyze the role of PTH signaling in mature osteoblasts/osteocytes during aging. Mice lacking PPR in osteocyte (Dmp1-PPRKO) display an age-dependent osteopenia characterized by a significant decrease in osteoblast activity and increase in osteoclast number and activity. At the molecular level, the absence of PPR signaling in mature osteoblasts/osteocytes is associated with an increase in serum sclerostin and a significant increase in osteocytes expressing 4-hydroxy-2-nonenals, a marker of oxidative stress. In Dmp1-PPRKO mice there was an age-dependent increase in p16Ink4a/Cdkn2a expression, whereas it was unchanged in controls. In vitro studies demonstrated that PTH protects osteocytes from oxidative stress-induced cell death. In summary, we reported that PPR signaling in osteocytes is important for protecting the skeleton from age-induced bone loss by restraining osteoclast’s activity and protecting osteocytes from oxidative stresses.