Monday, April 29, 2013

DNA damage drives mechanisms behind osteoporosis

As we age, there is a steady decline in the density and quality of our bones. This places us at greater risk for breaking a hip or sustaining a spinal compression fracture. Age-related cellular changes are responsible for this decline. When bone marrow stem cells atrophy, and bone forming osteoblasts wear out, and the bone-resorbing osteoclast cells get their "second wind"...we are faced with unrelenting skeletal deterioration and increased fragility.

The mechanism behind this deterioration is years of accumulated DNA damage. Research by Chen et al. reported in the Journal of Bone and Mineral Research demonstrates (in mice) that a failure to repair DNA damage is the driving force behind age-related bone loss. Constant bombardment by ultraviolet and ionizing radiation from space, and oxidative stress with free radical formation from the body's own metabolic activity are the main causes of cellular DNA damage. If this damage is not repaired, deterioration of cells, tissues, and organs, including bone, will lead to premature aging.  The purpose of Chen's study was to determine the exact mechanism by which a failure to repair DNA damage would lead to bone loss. What they found was that NF-kB, a key regulator of cell death and survival found in the nucleus of cells, is responsible for signaling the driving forces behind osteoporosis in response to accumulated DNA damage.

When proteins, cellular organelles and DNA sustain damage, and it is not repaired by natural repair mechanisms, the production of NF-kB increases. NF-kB initiates degenerative change, including bone loss.  Simple as that. If the DNA in our bone marrow stem cells is damaged and not repaired, NF-kB production within them increases causing them to atrophy and shrivel away. Without these stem cells there is no formation of bone-building osteoblasts. If the DNA in existing osteoblasts isn’t working properly, the resulting increase in NF-kB causes them to shut down. With no osteoblasts to produce new bone, bone density declines. And the kicker, when DNA is damaged and NF-kB production increases instead of leading to decreased osteoclast bone-resorbing activity it actually increases their bone degrading activity! Osteoclasts are the ONLY cells in your body whose sole function is to actually destroy the organ (bone) in which they reside. The osteoclast's ONLY action is to be destructive. An increase in NF-kB serves to increase the osteoclast's bone destructive actions and these are promoted by persistent cellular DNA damage.

This makes sense. Osteoclasts are destructive in nature and they are just doing what they are genetically engineered to do, destroy. As the body deteriorates from DNA damage, so does the skeleton. The combined effect of failing osteoblast bone-formation and increased osteoclast bone resorption leads to osteoporosis. This is why simply taking more calcium to fix osteoporosis doesn’t work. You must improve your body’s natural defenses against free radicals. You must limit DNA damage, improve repair mechanisms, and reduce NF-kB.

Alpha lipoic acid, N-acetyl cysteine, EGCG from green tea, resveratrol, and curcumin (from the spice turmeric) are all powerful natural inhibitors of inflammatory NF-kB. So powerful is curcumin that a recent study by Kim et al. in Molecular Nutrition and Food Research demonstrated its ability to block the proliferation of cancer by suppressing NF-kB.

Chen, Q., et al. 2013. DNA damage drives accelerated bone aging via and NF-kB-dependent mechanism. JBMR 28(5):1214-1228.

Kim, J.H., et al. 2012. Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-kB and NF-kB-reguated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitization, and suppressed osteoclastogenesis. Mol Nutr Food Res 56(3):454-465.
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