Increased adipogenesis in bone marrow but decreased bone mineral density in mice devoid of thyroid hormone receptors

Mice deficient for all known thyroid hormone receptors, TRα1−/−β−/− mice, display a clear skeletal phenotype characterized by growth retardation, delayed maturation of long bones and decreased trabecular and total bone mineral density (BMD; −14.6 ± 2.8%, −14.4 ± 1.5%). The aim of the present study was to investigate the molecular mechanisms behind the skeletal phenotype in TRα1−/−β−/− mice. Global gene expression analysis was performed on total vertebrae from wild-type (WT) and TRα1−/−β−/− mice using DNA microarray and the results were verified by real-time PCR. The mRNA levels of six genes (AdipoQ, Adipsin, Fat-Specific Protein 27 (FSP 27), lipoprotein lipase (LPL), retinol-binding protein (RBP) and phosphoenolpyruvate carboxykinase (PEPCK)) expressed by mature adipocytes were increased in TRα1−/−β−/− compared with WT mice. An increased amount of fat (225% over WT) due to an increased number but unchanged mean size of adipocytes in the bone marrow of TRα1−/−β−/− mice was revealed. Interestingly, the mRNA levels of the key regulator of osteoclastogenesis, receptor activator of NF- b ligand (RANKL), were dramatically decreased in TRα1−/−β−/− mice. In conclusion, TRα1−/−β−/− mice demonstrated increased expression of adipocyte specific genes and an increased amount of bone marrow fat. Thus, these mice have increased adipogenesis in bone marrow associated with decreased trabecular bone mineral density (BMD). One may speculate that these effects either could be caused by an imbalance in the differentiation of the osteoblast and the adipocyte lineages at the expense of osteoblastogenesis, or by independent effects on the regulation of both osteoblastogenesis and adipogenesis.