Journal article
Osteoblast-targeted suppression of PPARγ increases osteogenesis through activation of mTOR signaling
Stem cells (Dayton, Ohio), Vol.31(10), pp.2183-2192
10/2013
DOI: 10.1002/stem.1455
PMCID: PMC3812401
PMID: 23766271
Abstract
Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) is an essential transcription factor for adipocyte differentiation. In mesenchymal stem cells, PPARγ has been assumed to play a negative role in osteoblastic differentiation, by working in an adipogenesis dependent manner, due to the reciprocal relationship between osteoblast and adipocyte differentiation. However, the direct role of PPARγ in osteoblast function is not fully understood, due in part to inadequate model systems. Here, we describe an adenoviral-mediated PPARγ knockout system in which suppression of PPARγ in mesenchymal stem cells enhanced osteoblast differentiation and inhibited adipogenesis in vitro. Consistent with this in vitro observation, lipoatrophic A-ZIP/F1 mice, which do not form adipocytes, displayed a phenotype in which both cortical and trabecular bone was significantly increased compared with wild-type mice. We next developed an inducible osteoblast-targeted PPARγ knockout (Osx Cre/flox- PPARγ) mouse to determine the direct role of PPARγ in bone formation. Data from both in vitro cultures of mesenchymal stem cells and in vivo µCT analysis of bones suggest that suppression of PPARγ activity in osteoblasts significantly increased osteoblast differentiation and trabecular number. Endogenous PPARγ in mesenchymal stem cells and osteoblasts strongly inhibited Akt/mammalian target of rapamycin (mTOR)/p70S6k activity and led to decreased osteoblastic differentiation. Therefore, we conclude that PPARγ modulates osteoblast differentiation and bone formation through both direct and indirect mechanisms. The direct mode, as shown here, involves PPARγ regulation of the mTOR pathway, while the indirect pathway is dependent on the regulation of adipogenesis.
Details
- Title: Subtitle
- Osteoblast-targeted suppression of PPARγ increases osteogenesis through activation of mTOR signaling
- Creators
- Hongli Sun - University of MichiganJin Koo KimRichard Mortensen - University of MichiganLorraine P Mutyaba - Department of Clinical Studies‐New Bolton Center School of Veterinary Medicine and Department of Orthopaedic SurgeryPerelman School of MedicineUniversity of PennsylvaniaPhiladelphia Pennsylvania USAKurt D Hankenson - Department of Clinical Studies‐New Bolton Center School of Veterinary Medicine and Department of Orthopaedic SurgeryPerelman School of MedicineUniversity of PennsylvaniaPhiladelphia Pennsylvania USAPaul H Krebsbach - Materials Sciences (United States)
- Resource Type
- Journal article
- Publication Details
- Stem cells (Dayton, Ohio), Vol.31(10), pp.2183-2192
- DOI
- 10.1002/stem.1455
- PMID
- 23766271
- PMCID
- PMC3812401
- NLM abbreviation
- Stem Cells
- ISSN
- 1066-5099
- eISSN
- 1549-4918
- Grant note
- T32 DE007057 / NIDCR NIH HHS R01 AR054714 / NIAMS NIH HHS R01-DK-082481 / NIDDK NIH HHS R01-AR-054714 / NIAMS NIH HHS R01 DK082481 / NIDDK NIH HHS
- Language
- English
- Date published
- 10/2013
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Craniofacial Anomalies Research Center; Oral and Maxillofacial Surgery
- Record Identifier
- 9984367730702771
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