Brittle Bones Begone: New Findings Uncover Why Our Bones Get Weaker with Age

The Context: Our bones get more fragile as we age, leading to increased risk of disease or injury, but why exactly this happens on a cellular level is not well understood.

The Study: As we age, cellular signals that promote bone repair and development (in a biochemical cascade called ‘Notch’) increase abnormally, leading to more brittle bones. The study, co-led by NYSCF – Druckenmiller Fellow Sophie Morgani, PhD, of NYU, appears in Bone Research.

The Importance: Understanding the process underlying bone regeneration could help scientists develop strategies to prevent or repair it.

“Our population is rapidly aging, and bone health is such a pressing issue that we have to deal with,” said Dr. Morgani. “Although people rarely die from having a broken bone, it’s often the first event that can lead to a downward spiral of health.”

A Unique Tissue

“Bone is really cool as well because it’s one of the few tissues in a human that can fully regenerate,” remarked Dr. Morgani. “So normally if we get an injury in other tissues, it will heal, but you get a scar, whereas bone just fully regenerates as if it was never broken.”

The reason our bones can do this is because they have a reserve of stem cells that they draw from to maintain a healthy structure by turning into fat or bone tissue. As we age, however, these cells start turning into fat more so than bone, leaving the skeleton at a higher risk of injury, and researchers haven’t been exactly sure why this happens.

Inside the Bones

The team decided to examine the activity of genes in these stem cells as they aged, as this could perhaps point to clues as to why the switch occurs. By comparing young and old mouse bones, they noticed a certain process called ‘Notch signaling’ starts to go awry in older bones. Usually, Notch signaling reaches its peak when we are developing our tissues in the womb, but becomes less amplified in early life. As we age, however (and in diseases like cancer), Notch signaling is abnormally reactivated, and this can interfere with the stem cells’ ability to create new bone. 

Excitingly, blocking Notch signaling via genetic engineering in middle-aged mice helped restore bone formation, fortifying bone even more than in young mice.

And while modifying the Notch pathway could be difficult in humans due to its widespread residence throughout our tissues, the scientists are hopeful that targeting a protein called Ebf3 that carries the Notch signal forward could be an effective drug target.

“Our findings reveal that Notch in skeletal stem cells becomes abnormal with age, and that blocking it prevents age-related skeletal degeneration,” said corresponding study author Philipp Leucht, MD, PhD, the Raj-Sobti-Menon Associate Professor of Orthopedic Surgery in the Department of Orthopedic Surgery at NYU Langone Health in an article from NYU. “The reprogramming of adult stem cells as a source of bone-making cells in healing-compromised people has profound therapeutic potential, and we hope to confirm the value in future studies of Ebf3 as a drug target in preventing osteoporosis.”

“As a rising trainee in orthopedic surgery, I am intrigued by the molecular and cellular machinery that governs skeletal stem cell fate,” said first author Lindsey Remark, MD, PhD, a graduate student in the Leucht laboratory. “Our newly gained knowledge opens potential therapeutic avenues to overcome age-related bone loss by manipulating down-stream effectors for Notch signaling in these stem cells.”

Journal Article

Loss of Notch signaling in skeletal stem cells enhances bone formation with aging
Lindsey H. Remark, Kevin Leclerc, Malissa Ramsukh, Ziyan Lin, Sooyeon Lee, Backialakshmi Dharmalingam, Lauren Gillinov, Vasudev V. Nayak, Paulo El Parente, Margaux Sambon, Pablo J. Atria, Mohamed A. E. Ali, Lukasz Witek, Alesha B. Castillo, Christopher Y, Park, Ralf H. Adams, Aristotelis Tsirigos, Sophie M. Morgani & Philipp Leucht. 2023. Bone Research. DOI: https://doi.org/10.1038/s41413-023-00283-8