Targeting cellular senescence prevents age-related bone loss in mice

Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.

Errataetall:

CommentIn: Nat Rev Rheumatol. 2017 Nov;13(11):632. - PMID 28905853

Medienart:

E-Artikel

Erscheinungsjahr:

2017

Erschienen:

2017

Enthalten in:

Zur Gesamtaufnahme - volume:23

Enthalten in:

Nature medicine - 23(2017), 9 vom: 07. Sept., Seite 1072-1079

Sprache:

Englisch

Beteiligte Personen:

Farr, Joshua N [VerfasserIn]
Xu, Ming [VerfasserIn]
Weivoda, Megan M [VerfasserIn]
Monroe, David G [VerfasserIn]
Fraser, Daniel G [VerfasserIn]
Onken, Jennifer L [VerfasserIn]
Negley, Brittany A [VerfasserIn]
Sfeir, Jad G [VerfasserIn]
Ogrodnik, Mikolaj B [VerfasserIn]
Hachfeld, Christine M [VerfasserIn]
LeBrasseur, Nathan K [VerfasserIn]
Drake, Matthew T [VerfasserIn]
Pignolo, Robert J [VerfasserIn]
Pirtskhalava, Tamar [VerfasserIn]
Tchkonia, Tamara [VerfasserIn]
Oursler, Merry Jo [VerfasserIn]
Kirkland, James L [VerfasserIn]
Khosla, Sundeep [VerfasserIn]

Links:

Volltext

Themen:

82S8X8XX8H
Beta-Galactosidase
Casp8 protein, mouse
Caspase 8
Culture Media, Conditioned
EC 2.7.10.2
EC 3.2.1.23
EC 3.4.22.-
Janus Kinases
Journal Article
Nitriles
Pyrazoles
Pyrimidines
Ruxolitinib

Anmerkungen:

Date Completed 02.10.2017

Date Revised 09.11.2022

published: Print-Electronic

CommentIn: Nat Rev Rheumatol. 2017 Nov;13(11):632. - PMID 28905853

Citation Status MEDLINE

doi:

10.1038/nm.4385

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM274987953