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] |
---|
Links: |
---|
Themen: |
82S8X8XX8H |
---|
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 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM274987953 | ||
003 | DE-627 | ||
005 | 20231225004655.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231225s2017 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1038/nm.4385 |2 doi | |
028 | 5 | 2 | |a pubmed24n0916.xml |
035 | |a (DE-627)NLM274987953 | ||
035 | |a (NLM)28825716 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Farr, Joshua N |e verfasserin |4 aut | |
245 | 1 | 0 | |a Targeting cellular senescence prevents age-related bone loss in mice |
264 | 1 | |c 2017 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 02.10.2017 | ||
500 | |a Date Revised 09.11.2022 | ||
500 | |a published: Print-Electronic | ||
500 | |a CommentIn: Nat Rev Rheumatol. 2017 Nov;13(11):632. - PMID 28905853 | ||
500 | |a Citation Status MEDLINE | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
650 | 7 | |a Culture Media, Conditioned |2 NLM | |
650 | 7 | |a Nitriles |2 NLM | |
650 | 7 | |a Pyrazoles |2 NLM | |
650 | 7 | |a Pyrimidines |2 NLM | |
650 | 7 | |a ruxolitinib |2 NLM | |
650 | 7 | |a 82S8X8XX8H |2 NLM | |
650 | 7 | |a Janus Kinases |2 NLM | |
650 | 7 | |a EC 2.7.10.2 |2 NLM | |
650 | 7 | |a beta-Galactosidase |2 NLM | |
650 | 7 | |a EC 3.2.1.23 |2 NLM | |
650 | 7 | |a Casp8 protein, mouse |2 NLM | |
650 | 7 | |a EC 3.4.22.- |2 NLM | |
650 | 7 | |a Caspase 8 |2 NLM | |
650 | 7 | |a EC 3.4.22.- |2 NLM | |
700 | 1 | |a Xu, Ming |e verfasserin |4 aut | |
700 | 1 | |a Weivoda, Megan M |e verfasserin |4 aut | |
700 | 1 | |a Monroe, David G |e verfasserin |4 aut | |
700 | 1 | |a Fraser, Daniel G |e verfasserin |4 aut | |
700 | 1 | |a Onken, Jennifer L |e verfasserin |4 aut | |
700 | 1 | |a Negley, Brittany A |e verfasserin |4 aut | |
700 | 1 | |a Sfeir, Jad G |e verfasserin |4 aut | |
700 | 1 | |a Ogrodnik, Mikolaj B |e verfasserin |4 aut | |
700 | 1 | |a Hachfeld, Christine M |e verfasserin |4 aut | |
700 | 1 | |a LeBrasseur, Nathan K |e verfasserin |4 aut | |
700 | 1 | |a Drake, Matthew T |e verfasserin |4 aut | |
700 | 1 | |a Pignolo, Robert J |e verfasserin |4 aut | |
700 | 1 | |a Pirtskhalava, Tamar |e verfasserin |4 aut | |
700 | 1 | |a Tchkonia, Tamara |e verfasserin |4 aut | |
700 | 1 | |a Oursler, Merry Jo |e verfasserin |4 aut | |
700 | 1 | |a Kirkland, James L |e verfasserin |4 aut | |
700 | 1 | |a Khosla, Sundeep |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Nature medicine |d 1995 |g 23(2017), 9 vom: 07. Sept., Seite 1072-1079 |w (DE-627)NLM074659804 |x 1546-170X |7 nnns |
773 | 1 | 8 | |g volume:23 |g year:2017 |g number:9 |g day:07 |g month:09 |g pages:1072-1079 |
856 | 4 | 0 | |u http://dx.doi.org/10.1038/nm.4385 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 23 |j 2017 |e 9 |b 07 |c 09 |h 1072-1079 |