Research Paper Volume 12, Issue 14 pp 15121—15133

Megakaryocytes promote osteoclastogenesis in aging

Deepa Kanagasabapathy1, , Rachel J. Blosser1, , Kevin A. Maupin1, , Jung Min Hong2, , Marta Alvarez1, , Joydeep Ghosh3, , Safa F. Mohamad3, , Alexandra Aguilar-Perez2, , Edward F. Srour3, , Melissa A. Kacena1, , Angela Bruzzaniti2, ,

  • 1 Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
  • 2 Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, IN 46202, USA
  • 3 Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA

Received: January 25, 2020       Accepted: June 13, 2020       Published: July 7, 2020      

https://doi.org/10.18632/aging.103595
How to Cite

Copyright © 2020 Kanagasabapathy 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

Megakaryocytes (MKs) support bone formation by stimulating osteoblasts (OBs) and inhibiting osteoclasts (OCs). Aging results in higher bone resorption, leading to bone loss. Whereas previous studies showed the effects of aging on MK-mediated bone formation, the effects of aging on MK-mediated OC formation is poorly understood. Here we examined the effect of thrombopoietin (TPO) and MK-derived conditioned media (CM) from young (3-4 months) and aged (22-25 months) mice on OC precursors. Our findings showed that aging significantly increased OC formation in vitro. Moreover, the expression of the TPO receptor, Mpl, and circulating TPO levels were elevated in the bone marrow cavity. We previously showed that MKs from young mice secrete factors that inhibit OC differentiation. However, rather than inhibiting OC development, we found that MKs from aged mice promote OC formation. Interestingly, these age-related changes in MK functionality were only observed using female MKs, potentially implicating the sex steroid, estrogen, in signaling. Further, RANKL expression was highly elevated in aged MKs suggesting MK-derived RANKL signaling may promote osteoclastogenesis in aging. Taken together, these data suggest that modulation in TPO-Mpl expression in bone marrow and age-related changes in the MK secretome promote osteoclastogenesis to impact skeletal aging.

Abbreviations

MK: megakaryocyte; OB: osteoblast; OC: osteoclast; TPO: thrombopoietin; M-CSF: macrophage colony stimulating factor; RANKL: receptor activator of nuclear factor kappa-Β ligand; OPG: osteoprotegerin; SD: standard deviation.