title: Retinaldehyde dehydrogenase 1 deficiency inhibits PPARγ-mediated bone loss and marrow adiposity.
abstract: PPARγ, a ligand-activated nuclear receptor, regulates fundamental aspects of bone homeostasis and skeletal remodeling. PPARγ-activating anti-diabetic thiazolidinediones in clinical use promote marrow adiposity, bone loss, and skeletal fractures. As such, delineating novel regulatory pathways that modulate the action of PPARγ, and its obligate heterodimeric partner RXR, may have important implications for our understanding and treatment of disorders of low bone mineral density. We present data here establishing retinaldehyde dehydrogenase 1 (Aldh1a1) and its substrate retinaldehyde (Rald) as novel determinants of PPARγ-RXR actions in the skeleton. When compared to wild type (WT) controls, retinaldehyde dehydrogenase-deficient (Aldh1a1(-/-)) mice were protected against bone loss and marrow adiposity induced by either the thiazolidinedione rosiglitazone or a high fat diet, both of which potently activate the PPARγ-RXR complex. Consistent with these results, Rald, which accumulates in vivo in Aldh1a1(-/-) mice, protects against rosiglitazone-mediated inhibition of osteoblastogenesis in vitro. In addition, Rald potently inhibits in vitro adipogenesis and osteoclastogenesis in WT mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) respectively. Primary Aldh1a1(-/-) HSCs also demonstrate impaired osteoclastogenesis in vitro compared to WT controls. Collectively, these findings identify Rald and retinoid metabolism through Aldh1a1 as important novel modulators of PPARγ-RXR transactivation in the marrow niche.
authors: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Shriram
authors: S
authors: Nallamshetty
authors: Center for Clinical & Translational Research, Maine Medical Center Research Institute, Scarborough, ME, USA.
authors: Phuong T
authors: PT
authors: Le
authors: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Hong
authors: H
authors: Wang
authors: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Maya J
authors: MJ
authors: Issacsohn
authors: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: David J
authors: DJ
authors: Reeder
authors: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Eun-Jung
authors: EJ
authors: Rhee
authors: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Florian W
authors: FW
authors: Kiefer
authors: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Jonathan D
authors: JD
authors: Brown
authors: Center for Clinical & Translational Research, Maine Medical Center Research Institute, Scarborough, ME, USA.
authors: Clifford J
authors: CJ
authors: Rosen
authors: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: jplutzky@rics.bwh.harvard.edu.
authors: Jorge
authors: J
authors: Plutzky
mesh_terms: D015502:Absorptiometry, Photon; D050154:Adiposity / Q000235:genetics / Q000502:physiology; D000444:Aldehyde Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D047495:PPAR gamma / Q000378:metabolism*; D050697:Retinal Dehydrogenase; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000633:toxicity; D055114:X-Ray Microtomography
chemical_list: D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase
keywords: PPAR gamma; Retinaldehyde; Retinaldehyde dehydrogenase 1; Retinoid