3 research outputs found
Retinaldehyde dehydrogenase 1 deficiency inhibits PPARĪ³-mediated bone loss and marrow adiposity.
PPARĪ³, a ligand-activated nuclear receptor, regulates fundamental aspects of bone homeostasis and skeletal remodeling. PPARĪ³-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 PPARĪ³, 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 PPARĪ³-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 PPARĪ³-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 PPARĪ³-RXR transactivation in the marrow niche