Signaling Pathways in Skeletal Development and Metabolism

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Abstract

Osteoporosis, a disease characterized by low bone mass and microarchitectural deterioration, causes nine million debilitating fractures annually. An increase in bone resorption not adequately compensated by a corresponding increase in bone formation is the major cause of osteoporosis. Since current therapies have failed to effectively eliminate osteoporosis, there is an urgent need to discover novel mechanisms regulating bone resorption and formation and develop new therapeutic approaches to treat this disease. To that end, we have explored novel, non-canonical signaling mechanisms of two well-established regulators of bone: thyroid hormone (TH) and vitamin C (ascorbic acid, AA). Since previous studies have shown TH can induce browning of adipose tissue, and since bone marrow adipose tissue (MAT) quantity and metabolic activity are related to bone quality, we first tested whether TH signaling could induce browning of MAT. We found that activation of TH receptor (TR)β induced expression of browning genes in MAT, and these changes were associated with increased bone mineral density. Next, since non-canonical, nongenomic signaling pathways in which TRs exert cytoplasmic effects in addition to their direct genomic effects as nuclear transcription factors, we tested whether some TH effects on bone are mediated via a nongenomic TRβ–PI3K pathway. We found that disruption of this TRβ–PI3K pathway reduced bone formation and mass and increased MAT in mice, and this nongenomic pathway was required for TRβ to induce osteoblast differentiation. Similarly, AA, a well-known regulator of osteoblast differentiation, is required for skeletal growth and development, and AA deficiency is implicated in osteoporotic fractures. Many AA effects on bone are mediated via prolyl hydroxylase domain-containing protein (PHD)2. Since AA induces DNA demethylation via the ten-eleven translocases (TETs), and since PHD2 is a member of the same enzyme family as the TETs, we tested whether AA induces osteoblast differentiation via DNA demethylation. We found that AA does induce demethylation in promoter regions of osteoblast differentiation genes, and this effect may be mediated via PHD2. Further elucidation of these novel nongenomic TH and epigenetic vitamin C signaling pathways will lead to many new druggable targets for the treatment and prevention of osteoporosis.

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