Author: Farr JN1, Fraser DG1, Wang H2, Jaehn K3, Ogrodnik MB1, Weivoda MM1, Drake MT1, Tchkonia T1, LeBrasseur NK1, Kirkland JL1, Bonewald LF3, Pignolo RJ2, Monroe DG1, Khosla S1
Affiliation: <sup>1</sup>Robert and Arlene Kogod Center on Aging and Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, MN, 55905.
<sup>2</sup>Departments of Orthopaedic Surgery and Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104.
<sup>3</sup>Department of Oral Biology, University of Missouri-Kansas City, School of Dentistry, Kansas City, MO, 64108.
Conference/Journal: J Bone Miner Res.
Date published: 2016 Jun 24
Other:
Special Notes: doi: 10.1002/jbmr.2892. [Epub ahead of print] , Word Count: 340
Cellular senescence is a fundamental mechanism by which cells remain metabolically active yet cease dividing and undergo distinct phenotypic alterations, including upregulation of p16Ink4a , profound secretome changes, telomere shortening, and decondensation of peri-centromeric satellite DNA. Because senescent cells accumulate in multiple tissues with aging, these cells and the dysfunctional factors they secrete, termed the senescence-associated secretory phenotype (SASP), are increasingly recognized as promising therapeutic targets to prevent age-related degenerative pathologies, including osteoporosis. However, the cell type(s) within the bone microenvironment that undergoes senescence with aging in vivo has remained poorly understood, largely because previous studies have focused on senescence in cultured cells. Thus, in young (6-month) and old (24-month) mice, we measured senescence and SASP markers in vivo in highly enriched cell populations, all rapidly isolated from bone/marrow without in vitro culture. In both females and males, p16Ink4a expression by rt-qPCR was significantly higher with aging in B cells, T cells, myeloid cells, osteoblast progenitors, osteoblasts, and osteocytes. Further, in vivo quantification of senescence-associated distension of satellites (SADS), i.e., large-scale unraveling of peri-centromeric satellite DNA, revealed significantly more senescent osteocytes in old compared to young bone cortices (11% versus 2%, p < 0.001). In addition, primary osteocytes from old mice had 6-fold more (p < 0.001) telomere dysfunction-induced foci (TIFs) than osteocytes from young mice. Corresponding with the age-associated accumulation of senescent osteocytes was significantly higher expression of multiple SASP markers in osteocytes from old versus young mice, several of which also showed dramatic age-associated upregulation in myeloid cells. These data demonstrate that with aging, a subset of cells of various lineages within the bone microenvironment become senescent, although senescent myeloid cells and senescent osteocytes predominantly develop the SASP. Given the critical roles of osteocytes in orchestrating bone remodeling, our findings suggest that senescent osteocytes and their SASP may contribute to age-related bone loss. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
KEYWORDS: Aging; animal models; cell/tissue signaling; osteocytes
PMID: 27341653 [PubMed - as supplied by publisher]