Transcriptional Changes and Preservation of Bone Mass in Hibernating Black Bears

Abstract

Physical inactivity leads to losses of bone mass and strength in most mammalian species. In contrast, hibernating bears show no bone loss over the prolonged periods (4 - 6 months) of immobility during winter, which suggests that they have adaptive mechanisms to preserve bone mass and structure. To identify transcriptional changes that underlie molecular mechanisms preventing disuse osteoporosis, we conducted a large-scale gene expression screening in trabecular bone, ilium, of black bears, comparing hibernating and summer active animals using next generation sequencing of the transcriptome. A total of 2,466 differentially expressed genes (FDR < 0.05) were up-regulated and 2,938 genes down-regulated during hibernation. Gene set enrichment analysis showed a coordinated down-regulation of genes involved in bone resorption, osteoclast differentiation and osteoclast signaling as well as apoptosis during hibernation. In contrast, no significant enrichment indicating directional changes in gene expression was detected in the gene sets of ossification (bone biosynthesis), osteoblast signaling and differentiation in bone of hibernating bears. Unanticipated under general metabolic suppression of hibernation, our study revealed significant and coordinated transcriptional induction of gene sets involved in aerobic energy production including the fatty acid beta oxidation, tricarboxylic acid cycle, oxidative phosphorylation, mitochondrial metabolism, biogenesis and turnover during hibernation. Mitochondrial oxidation and biogenesis were likely up-regulated by transcriptionally induced AMPK/PGC1α pathway, upstream master stimulator of mitochondrial function. We also found down-regulation of genes involved in immune response including both innate and adaptive immunity in bone marrow/bone of hibernating bears. Coordinated transcriptional suppression of bone resorption, osteoclast signaling and apoptosis genes implies decrease in resorption that preserves bone mass through the prolonged periods of immobility of hibernation.