Chondrocyte‐like nested cells in the aged intervertebral disc are late‐stage nucleus pulposus cells

Abstract

Aging is a major risk factor of intervertebral disc degeneration and a leading cause of back pain. Pathological changes associated with disc degeneration include the absence of large, vacuolated and reticular‐shaped nucleus pulposus cells, and appearance of smaller cells nested in lacunae. These small nested cells are conventionally described as chondrocyte‐like cells; however, their origin in the intervertebral disc is unknown. Here, using a genetic mouse model and a fate mapping strategy, we have found that the chondrocyte‐like cells in degenerating intervertebral discs are, in fact, nucleus pulposus cells. With aging, the nucleus pulposus cells fuse their cell membranes to form the nested lacunae. Next, we characterized the expression of sonic hedgehog (SHH), crucial for the maintenance of nucleus pulposus cells, and found that as intervertebral discs age and degenerate, expression of SHH and its target Brachyury is gradually lost. The results indicate that the chondrocyte‐like phenotype represents a terminal stage of differentiation preceding loss of nucleus pulposus cells and disc collapse.

Differential Effect of Long-Term Systemic Exposure of TNFα on Health of the Annulus Fibrosus and Nucleus Pulposus of the Intervertebral Disc

“…This result suggests that NP cell vacuoles may contribute to the DHI measurement. Cell size is particularly relevant to degenerative disc disease, because smaller chondrocyte‐like cells are associated with aging and degeneration . The increase in cell band size in the lumbar region is consistent with a recent study involving overexpression of TNFα.…”

“…Low back pain (LBP) and associated intervertebral disc degeneration is a widespread, costly, and complex medical condition affecting a huge proportion of the population . As the disc degenerates with age or disease, the nucleus pulposus (NP) becomes more fibrotic, and cells transition from a vacuolated notochordal phenotype to one that resembles hypertrophic chondrocytes . In concert with these cellular and extracellular matrix changes, the dramatic increase in interleukin‐1β (IL‐1β) and tumor necrosis factor alpha (TNFα) expression is correlated with severity of disc degeneration .…”

“…(1)(2)(3)(4) As the disc degenerates with age or disease, the nucleus pulposus (NP) becomes more fibrotic, and cells transition from a vacuolated notochordal phenotype to one that resembles hypertrophic chondrocytes. (5)(6)(7) In concert with these cellular and extracellular matrix changes, the dramatic increase in interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNFα) expression is correlated with severity of disc degeneration. (8) These cytokines are thought to further promote disc degeneration by activating matrix metalloproteinases (MMPs).…”

Autophagy and mTOR signaling during intervertebral disc aging and degeneration

“…8,9 A more recent article has found that chondrocyte-like cells are derived from disc NP cells during degeneration, the phenotype of which represents a terminal stage of differentiation preceding the loss of NP cells and disc collapse. 11 Notochordal cell-conditioned medium protects non-notochordal cells from apoptosis and inflammation. 12 In addition, notochordal cells produce larger amounts of proteoglycans than non-notochordal cells 13 and can stimulate non-notochordal cells to produce proteoglycans.…”

“…Notochordal cells only exist during the first 10 years of human life and are subsequently replaced by non‐notochordal, chondrocyte‐like cells of unknown provenance . A more recent article has found that chondrocyte‐like cells are derived from disc NP cells during degeneration, the phenotype of which represents a terminal stage of differentiation preceding the loss of NP cells and disc collapse . Notochordal cell‐conditioned medium protects non‐notochordal cells from apoptosis and inflammation .…”