Investigating the Role of the Hdac3 Co-Repressor Complex in Glucocorticoid Signaling-Mediated Bone Marrow Lipid Storage with Age

Abstract

Aging bone is characterized by loss of tissue density, marrow fat accumulation, and dysregulated bone marrow stromal cell (BMSC) differentiation. The contribution of the epigenetic regulator histone deactylase 3 (Hdac3) is of increasing interest in bone biology. Hdac3 expression decreases with aging, and the current model for conditional deletion of Hdac3 in Osterix-expressing osteoprogenitor cells (Hdac3-CKOOsx) exhibited an aged bone phenotype in young mice along with the novel finding of osteoblastic (Runx2+ osteogenic cells) lipid droplet storage. In addition, bone-specific loss of Hdac3 activity increases expression of the glucocorticoid (GC)-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (Hsd11b1), suggesting a mechanism for the increased lipid accumulation in aged and Hdac3-deficient BMSC-derived osteoblasts. The cofactor nuclear receptor corepressor 1 (NCoR1), which mediates Hdac3 enzymatic activity in a co-repressor complex (CRC), was proposed as a regulator of Hdac3 activity in bone. Both Hdac3 and NCoR1 expression decreased in aged osteoblasts, and the two factors exhibited synergy in downregulating the promoter activity of glucocorticoid-responsive elements. Because of the relationship between increased GC signaling and osteoporosis, the glucocorticoid receptor (GR) was investigated as a mediator of the marrow fat phenotype, with the hypothesis that loss of GR function in bone would be protective against common forms of osteoporosis. Chronic caloric restriction in WT and GR-deficient (GR-CKOOsx) mice was used as a short-term stressor to induce an osteoporotic phenotype, while aging of GR-deficient mice (where Hdac3 CRC expression naturally decreases) was used as a biologically-relevant model for dual loss of Hdac3 and the GR. Surprisingly, the loss of GR function in osteoprogenitors exacerbated bone loss and marrow fat accumulation in both models—and induced a chronic stress phenotype by increasing cellular bioenergetics and whole-body metabolic rate—providing evidence of a role for the GR in facilitating healthy bone maintenance as well as evidence for compensatory mechanisms that regulate bone biology through GC signaling. GR-deficient bone also induced changes to whole-body physiology (e.g., sarcopenia, decreased physical activity, metabolic dysfunction) that further demonstrate the intricacies of bone as an endocrine organ. The current study provides new avenues to investigate cell signaling, bioenergetics, and tissue crosstalk in osteoporotic bone.