Cold exposure reduces trabecular and cortical bone mass in wildtype and <i>Dio2</i> -deficient mice

Bone remodeling, mediated by bone-forming osteoblasts and bone-resorbing osteoclasts, is a physiologically relevant process controlled by several local and systemic regulatory mechanisms. Recent evidence in mice has suggested that it is also affected by housing temperature, which provides a basis to identify novel molecular regulators of bone remodeling. Here, we compared the skeletal phenotype of mice housed at thermoneutral (30 °C), room (22 °C), or cold (6 °C) temperature for 1 or 4 weeks. We observed that cold exposure for 1 week differentially affected osteoclastogenesis and osteoblast activity, which caused a significant reduction of trabecular number and cortical thickness after 4 weeks. Cold exposure is known to induce type II iodothyronine deiodinase (DIO2) expression in thermogenic adipose tissues. Because this enzyme catalyzes the deiodination of T4 to the active thyroid hormone T3, we addressed the question whether the cold-induced bone loss depends on DIO2. Importantly, however, we found that Dio2 deficiency in male and female mice did not affect the cold-induced reduction of trabecular and cortical bone mass, demonstrating that this process does not depend on thyroid hormone activation. To identify potential metabolic differences between the different groups of mice, we additionally performed lipidomic analyses. Here, we observed a remarkable reduction of specific lipid species after cold exposure, suggesting that either the systemic catabolic metabolism or the decrease of specific lipid species cause cold-induced bone loss. Taken together, although our data demonstrate that sustained cold exposure has a remarkable negative impact on bone mass, future studies are needed to identify causative molecules.