Scientists at the University of Rochester are delving into one of the long-standing questions in medical science: why and how do bones weaken with age? Supported by a $2 million grant from the National Institute of Aging, the research team, led by Dr. Roman Eliseev, is working to uncover the cellular processes behind bone loss, hoping to pave the way for new treatments for osteoporosis.
Osteoporosis, a condition that causes bones to become fragile and prone to fractures, affects 10 million Americans and results in about 2 million fractures annually. Yet, despite its prevalence, much remains unknown about the precise mechanisms that lead to the decline in bone density. Eliseev, an associate professor at the University’s Center for Musculoskeletal Research, aims to shed light on whether changes in energy metabolism within bone cells contribute to this deterioration.
“Bone health is a complex, lifelong process,” Eliseev said. “Bones constantly break down and regenerate, but in aging, this balance shifts, leading to more bone loss than new formation. Our goal is to understand why this happens.”
Existing therapies for osteoporosis, such as hormone replacement and medications like bisphosphonates, can slow bone loss or stimulate new bone growth, but they come with limitations and often high costs. Eliseev’s research seeks to go beyond these treatments by investigating the metabolic changes that occur in the cells responsible for bone formation, known as osteoblasts.
Osteoblasts play a key role in maintaining skeletal health by producing collagen and depositing minerals to form new bone tissue. However, as people age, these cells become less efficient, which leads to decreased bone formation. Eliseev’s research focuses on how osteoblasts metabolize nutrients to fuel their activity and how these processes change with aging.
“We’ve long known that bone loss isn’t just tied to hormonal changes, like those that occur after menopause,” Eliseev explained. “Bone mass peaks in a person’s 30s and starts to decline in both men and women well before hormonal shifts. This suggests other factors are at play, likely within the cells themselves.”
At the core of Eliseev’s research is the question of how osteoblasts generate energy to form new bone. For decades, scientists believed that glucose metabolism, specifically aerobic glycolysis, was the primary pathway by which bone cells produced energy. However, recent findings by Eliseev and his team suggest that oxidative phosphorylation, a process involving mitochondria and oxygen, is equally critical for osteoblast function.
“We used modern tools to explore metabolic pathways in ways that weren’t possible in the past,” Eliseev said. “We discovered that, in addition to glucose, osteoblasts also rely heavily on glutamine and fatty acids as energy sources. Interestingly, much of the glucose osteoblasts consume doesn’t get converted to lactate as previously thought. Instead, it fuels a process called the Pentose Phosphate Pathway, which is essential for producing cellular building blocks and maintaining cell health.”
As people age, this metabolic process becomes less efficient, which may be a key factor in the weakening of bones over time. “In aging, glucose’s role in the Pentose Phosphate Pathway decreases, which may explain why osteoblasts become less effective at forming new bone,” Eliseev said.
Eliseev’s work seeks to resolve a decades-old debate in the field of bone metabolism: whether bone cells rely more on aerobic glycolysis or oxidative phosphorylation to generate energy. His research indicates that both processes are important, and disruptions in either one could contribute to the development of osteoporosis.
“Bone cells, like muscle and heart cells, need oxygen to function properly,” Eliseev noted. “Our findings show that while glycolytic metabolism plays a role, oxidative metabolism is equally crucial for bone cell activity.”
The implications of this research could be far-reaching. By better understanding how energy metabolism affects bone health, Eliseev hopes to identify new therapeutic targets that go beyond current treatments for osteoporosis. His team has already demonstrated that they can alter metabolic pathways in mice to improve bone regeneration, a promising step toward developing therapies for humans.
“There are already drugs that can modify the metabolic pathways we’re studying,” Eliseev said. “What we learn from this project could eventually lead to treatments that help prevent excessive bone loss by correcting the energy metabolism in osteoblasts, offering a new approach alongside existing therapies.”
The NIH grant will enable Eliseev’s team to delve deeper into the basic science of bone aging and metabolism, with the long-term goal of translating these findings into clinical treatments for osteoporosis.
“We’re building on the legacy of research that began here at the University of Rochester in the 1970s,” Eliseev said, referencing the work of pioneering bone researcher William Neuman. “By expanding on his discoveries, we hope to bring new insights into how bones age and develop innovative strategies to help people maintain their bone health as they grow older.”
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