by Elizabeth Hofheinz, M.P.H., M.Ed.
If a disc went wandering for the fountain of youth, it might just end up at the lab of Chitra Dahia, Ph.D. at Hospital for Special Surgery (HSS) in New York.
Dr. Dahia, who is devoted to the intricacies of disc regeneration, told OSN, “Traditionally, the focus has been on degenerated discs rather than understanding the state of a healthy disc, and what changes leads to its pathological state. But our lab is asking questions such as, ‘What are the signaling pathways that keep a disc healthy (maintaining a certain number of cells, the health of these cells, preventing them from dying, disc innervation, etc.)?’ In part, we concentrate on sonic hedgehog, Wnt, BMP and TGFβ signaling pathways, to understand their role during the neonatal period, a time of continued development for all organs and tissues in the body.” And since the precursors of the nucleus pulposus—that form the center of the disc—is the key regulator of embryogenesis and patterning called ‘notochord.’ Notochord is important because it provides mechanical strength to the embryo, acts as a signaling center and manufactures a protein called sonic hedgehog. We were the first to show that postnatal nucleus pulposus cells also make sonic hedgehog, which regulates the disc growth in young mice.”
Reawakening the cells
“One of our recent studies found that in the sacral disc, known to mineralize by skeletal maturity, the expression of sonic hedgehog decreases. However, when we overactivated the hedgehog pathway in a subset of the nucleus pulposus cells, we found that the activation of the hedgehog pathway had not only reactivated the nucleus but the surrounding cells as well. We showed with statistical significance that the hedgehog signaling is important and that activation of only a few cells can reverse the phenoytype, meaning that there are only a few cells that we need to turn on or re-awaken.”
In another paper conducted with Todd Albert, M.D., Surgeon-in-Chief Emeritus at HSS, Dr. Dahia showed that nucleus pulposus cells differentiate into a pathological phenotype described as chondrocyte-like in the literature. “We found that as intervertebral discs age and degenerate, sonic hedgehog expression gradually subsides. It turns out that the chondrocyte‐like phenotype is the ‘last stop’ before the loss of nucleus pulposus cells and collapse or fibrosis of the disc.”
So the next logical question is, “Why do they differentiate?”
Dr. Dahia: “We are now testing the role of sonic hedgehog signaling. It is high in healthy cells of young mice and decreases with age. So, is the loss of this signaling causing these pathological phenotypic changes and results in disc inflammation? Time will tell—as will our studies using conditional genetic knockout mice where we make the disc age sooner than it would have normally.”
In 2019 Dr. Dahia and her colleagues found that when a disc degenerates with age, the mice had pain sensitivity. “If the disc degeneration is making mediators of pain, then that could explain the sensitivity to pain. We are now following up with that, studying patient samples from spine surgery and determining if what we found in mice holds true for humans.”
Fundamentally, says Dr. Dahia, they are trying to gain an in-depth understanding of why some degenerated discs are painful, while other are not. “Maybe whatever the degenerating disc is making is mediating the pain. And maybe young and healthy discs have a molecular profile, i.e., signals that are preventing the expression of the genes that cause inflammation. We want to know what changes are occurring in the disc that cause it to degenerate and result in pain symptoms.”
Ultimately, Dr. Dahia’s lab will be able to translate this work and develop approaches for the regeneration of intervertebral discs and for the treatment of lower back and disc related disorders.