Balancing Bones: Epigenetic Regulators Are Important for Maintaining Bone Homeostasis
Walking the dog is not typically considered a dangerous task, but when an unexpected tug on the leash leads to a fall and a broken hip, it certainly becomes one. As we age, the balance between the formation of new bone and the removal of old bone shifts. New bone formation becomes slower, while bone removal – also called resorption – persists, leading to weaker bones and thus a greater risk of a break. In diseases like osteoporosis, however, this balance is tipped even further, such that the rate of bone loss exceeds the rate of bone formation so much that a movement as small as a cough can lead to a fractured bone .
Multiple biological signaling pathways have been shown to regulate the bone formation and resorption process, including the WNT/β-catenin pathway and the RANK/RANKL/OPG system. Prior work has shown that oxidative stress – an imbalance between the production of reactive oxygens, which can damage cells, and the antioxidants that remove them – can disrupt these pathways and lead to adverse effects on bone homeostasis . Because oxidative stress can affect epigenetic mechanisms like DNA methylation and post-translational histone modifications, a new study by Vrtačnik et al set out to ask how oxidative stress and a related condition called hypoxia affect the expression of epigenetic regulators in healthy people versus patients with osteoporosis or osteoarthritis.
Vrtačnik et al first asked how oxidative stress and hypoxia effect gene expression in human osteosarcoma (HOS) cells. Using quantitative real-time PCR (qPCR), they found that genes known to alter their expression in response to oxidative stress or hypoxia changed their expression as expected when treated with hydrogen peroxide (H2O2) to induce oxidative stress, or hypoxia mimetic deferoxamine (DFO) to induce hypoxia. To identify chromatin-modifying genes that were effected by oxidative stress and hypoxia, they investigated the expression profiles of 48 genes encoding chromatin-modifying enzymes and osteoblast associated proteins in HOS cells treated with H2O2 or DFO. They continued their analysis with those genes that had the greatest changes in expression compared to untreated HSO cells.
Looking at both 24 and 72 hours after treatment with H2O2 or DFO, the researchers found that the epigenetic enzymes that were most affected were HAT1, a histone acetyl transferase; HDAC6, HDAC7, HDAC9, and SIRT1, which are histone deacetylases; and MBD1 and DNMT3A, both of which are enzymes associated with DNA methylation. From these genes, they chose to look at the expression of HAT1, HDAC6, HDAC9, MBD1, and DNMT3A in addition to the lysine acetyl transferase, KAT5, in human tissue samples of healthy, osteoporosis, and osteoarthritis patients. They found that expression of KAT5, HAT1, HDAC6, DNMT3A, and MBD1 decreased in patients with osteoporosis, and that expression of KAT5, HAT1, HDAC6, and MBD1 decreased in patients with osteoarthritis. The researchers also showed that the expression of these genes in patient tissues correlated with bone mineral density and indicators of oxidative stress.
While preliminary, this study shows that environmental factors such as oxidative stress can affect the expression of epigenetic regulators in human cells, which in turn, can alter the expression of genes important for maintaining bone homeostasis. In addition, the authors show that there is a correlation between a decrease in expression of chromatin regulators and patients with osteoporosis or osteoarthritis. This study and future studies of the epigenetic mechanisms that regulate bone formation and resorption will hopefully lead to new and more effective treatments for people with bone homeostatic diseases, allowing them to run, laugh, and live their lives without fear for their bones.
Original article: Vrtačnik P, Zupan J, Mlakar V, Kranjc T, Marc J, Kern B, Ostanek B (2018). Epigenetic enzymes influenced by oxidative stress and hypoxia mimetic in osteoblasts are differentially expressed in patients with osteoporosis and osteoarthritis. Sci Rep, 8(1):16215. DOI: 10.1038/s41598-018-34255-4.
 Mayo Clinic (2018). Osteoporosis. Mayo Foundation for Medical Education and Research. https://www.mayoclinic.org/diseases-conditions/osteoporosis/symptoms-causes/syc-20351968.