Reduced bone mass and mineral density are common characteristics in aging bone, leading to a significant increase of fracture risk in the elderly. Osteoporosis-related fractures most commonly occur in the hip, wrist or spine. Bones are in a constant state of renewal — new bone is made and old bone is broken down. When you’re young, your body makes new bone faster than it breaks down old bone and your bone mass increases. Most people reach their peak bone mass by their early 20s. As people age, bone mass is lost faster than it’s created. There is no cure for osteoporosis and typical treatments are bisphosphonate or hormonal therapy. Given the side and limited effects of todays therapies alternative solutions are still needed.
As mitochondria deteriorate, they lose capacity for oxidative phosphorylation, biosynthesis, and ion transport. The relationship between mitochondrial dysfunction and aging has been studied and demonstrated in many tissues, including the brain, muscle, and cardiovascular system. This led researchers to hypnotize that well functioning mitochondria may be important to bone health since bone tissue has high energy demands due to the continuous remodeling.
The researchers focussed on observing whether mitochondrial functioning in bone tissue is impaired via opening of the mitochondrial permeability transition pore (MPTP) in bone. The MPTP is a large non-selective pore regulated by cyclophilin D (CypD) that disrupts mitochondrial membrane integrity. MPTP involvement has been established in degenerative processes in heart, brain, and muscle. The goal of the study was to determine whether mitochondria are impaired in aging bone and to see if protecting mitochondria from the MPTP opening mechanism protects against bone loss. The last part can be modeled via CypD knockout mice which prevents MPTP opening.
The research work showed firstly that bone loss in aging mice coincides with metabolic changes in bone tissue indicative of mitochondrial dysfunction. Increased mitochondrial swelling in osteocytes, indicating increased MPTP activity was observed.
Also bones of 13-month-old mice showed a significant increase in glycolytic intermediates compared to 3-month-old mice, while mitochondrial TCA cycle intermediates were not significantly changed. This accumulation of glycolytic intermediates without a corresponding increase in TCA cycle intermediates likely indicates decreased mitochondrial function, as the glycolytic products are not being further utilized in mitochondria. The researchers also were able to detect cellular nucleotides and redox compounds. Importantly, they detected significant elevations of both ATP and AMP in bones of 13-mo-old mice compared to 3-mo-old mice, leading to a significant increase in the Energy Charge (ATP + ½ADP/ATP + ADP + AMP) parameter. The elevated Energy Charge is an indicator of lower cell energy demand and compromised energy metabolism. NAD+/NADH ratio is known to be significantly decreased in aging and in agreement with this, the 13-mo-old bone samples had significantly lower levels of NAD+ with similar levels of NADH. These changes were observed also at 18-months but more pronounced.
In CypD KO mice, which prevents MPTP opening, at 13 or 18 months an aging bone phenotype was not detected suggesting a link between bone loss and mitochondrial functioning. In addition it was noted that there were no significant changes in the TCA cycle intermediates, nucleotides, or the energy charge indicating that there were no obvious metabolic disturbances in these tissue samples when compared to 3-month-old. There was a decrease in NADH levels, likely indicating that the mitochondrial electron transport chain and/or NADH consuming enzymes are active and mitochondria are healthy and functional.The NAD+/NADH ratio however was not significantly changed in 13- versus 3-month bone. Also at 18-months, CypD KO mouse bone structure was still not significantly different from that at 3-months.
All together this study in mice strongly indicates that protecting mitochondrial function is linked to improved bone health in aging. This opens up a target for new bone therapeutics.
You can find the study here.