New, Powerful Insight Into Bone Aging and Repair From NYU

In a sign of hope for those of us with deteriorating bones (all of us?), new research has found that by blocking the Notch signaling pathway in aging skeletal stem cells (mouse model), there was a “massive increase” in bone mass and bone-healing ability.

The work, “Loss of Notch signaling in skeletal stem cells enhances bone formation with aging,” conducted by a team from NYU Langone in Manhattan, appears in the September 27, 2023, edition of Bone Research, a Nature journal.

Past studies, wrote the NYU researchers, show that skeletally mature or elderly stem and progenitor cells tend to become cells that make fat more often than bone. So, they wondered, would a genetically engineered mouse, which lacks the protein that is part of the Notch signaling chain, Nicastrin, nudge these stem and progenitor cells away from an adipose tissue tendency and toward bone building?

The Notch signaling chain, incidentally, refers to cell-cell communication or signaling where transmembrane ligands on one cell activate transmembrane receptors on a juxtaposed (adjacent?) cell.

Using mice that lacked the essential protein for Notch signaling, the NYU team organized their study and…found that, indeed, as hypothesized, the stem and progenitor cells, when not affected by the protein Nicastrin and therefore Notch signaling, do tend to choose the bone-making cell pathway, and increased bone formation “even beyond that seen in young mice.”

“Our findings reveal that Notch in skeletal stem cells becomes abnormal with age, and that blocking it prevents age-related skeletal degeneration,” says corresponding study author Philip Leucht, M.D., Ph.D. the Raj-Sobti-Menon Associate Professor in the Department of Orthopedic Surgery and Cell Biology at NYU Langone Health.

“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.”

When OTW asked why the molecular mechanisms that underlie this detrimental transformation are largely unknown, Dr. Leucht noted, “Loss of stem cell function with aging is a multi-factorial process, and therefore we all assume that finding a single miracle cure is unlikely to happen.”

“When we come across data like the one presented in this manuscript, where manipulation of one single pathway reverses an entire phenotype, this catches us by surprise.”

“Most likely, if we succeed to translate this into humans, the gain of bone formation seen in mice will not be shown in humans. Rather, we will see a more subtle but still substantial gain in bone mass.”

“Only if other aspects of aging are addressed at the same time, will we be able to reverse the skeletal aging phenotype.”

Unexpected Side Effects (in the Mouse Model)?

Dr. Leucht noted one logical side effect, but which, in fact, had a favorable outcome in the mouse model. “The amount of bone formation is incredible, yet not detrimental to the mouse. Our first thought was that hematopoiesis, which happens in the bone marrow cavity would be affected by the increase in bone in the marrow space.”

“But our data show that this is not the case. In humans, we would not like to reproduce a massive increase like the one seen in mice. Rather a subtle increase in trabecular bone volume in the metaphases of long bones and in the spine would have the greatest benefit for patients with osteoporosis, as those are the locations most prone to osteoporotic fragility fractures.”

“We are currently in the process of identifying druggable targets that would allow us to translate this to humans. So more on that in the next few years. It is hard to predict if we can devise a safe strategy for translation, but we are hopeful.”