Intervertebral disc degeneration (IDD) underlies many spinal disorders resulting in debilitating back pain, disability, and tremendous economic loss. Several etiologic factors of IDD have been identified, including aging. Loss of disc matrix proteoglycans (PG), an important class of structural protein for counteracting load, is a universal feature of IDD. With aging, there is progressive loss of disc matrix proteoglycans, but the precise mechanisms by which aging promotes disc PG loss IDD are poorly understood. This represents the next major gap in disc aging research. Disc PG loss is primary driven by cells with perturbed PG homeostasis, whereby PG synthesis is down regulated while PG catabolism is up regulated. Senescent cells accumulate in various tissues and have been thought to promote aging. Elevated senescent cells have also been detected in aged discs, but it is not known if these cells exhibit perturbed PG homeostasis that causes net PG loss during aging. Recent studies demonstrated that stress-induced senescent fibroblasts secrete numerous inflammatory cytokines and matrix proteinases, a feature termed senescence associated secretory phenotype (SASP), which can have profound paracrine catabolic effects on neighboring cells and extracellular matrix. We recently discovered from studies using the DNA repair-deficient mouse model of accelerated aging (Ercc1-/? mice) that DNA damage is a key driver of age-related disc PG loss and that NF-?B pathway is important in this process. Because DNA damage and NF-?B activity are important for the formation of cellular senescence, we hypothesized that NF-?B mediates DNA damage-induced cellular senescence, which perturbs disc PG homeostasis, leading to PG loss and age-related IDD. To test our hypothesis, we proposed to determine in Aim #1: the role of NF-?B in mediating the establishment of cellular senescence in discs of mice genetically depleted of the p65 subunit of NF-?B, Aim #2: the metabolic phenotype of senescent disc cells as it relates to PG homeostasis and SASP, and Aim #3: the causal role of cellular senescence in driving disc aging using genetic mouse models manipulated to reduce the level of cellular senescence. Successful completion of the proposed experiments will determine whether cellular senescence promotes disc aging and provide a specific target for therapeutic interventions for delaying the onset or ameliorating the severity of age-related IDD, the incidence of which is expected to rise rapidly with the fast growing aging population. I will be leading the collaborative team effort to tackle this proposed research. Our well- integrated team consists of Laura Niedernhofer, a mouse geneticist and a leader in DNA repair/aging research, Paul Robbins, the NF-?B expert, Peter Roughley, the aggrecan biochemist, Gwendolyn Sowa, a mechanobiologist with a specialty in disc gene expression profiling, and James Kang, spine surgeon and disc researcher who will provide human surgical disc specimen for analysis.
This project aims at understanding the cellular mechanisms of how aging contributes to the loss of disc matrix proteoglycan (PG) leading to intervertebral disc degeneration (IDD) and many debilitating spine-related disorders. The proposed experiments, if successfully completed, will identify cellular senescence as a specific disc cell subpopulation primarily responsible for driving age-related matrix PG loss and other degenerative changes in the intervertebral discs. This information will provide a novel cellular target for the development of therapeutic interventions aim at delaying the onset of age-related IDD.
|Patil, Prashanti; Niedernhofer, Laura J; Robbins, Paul D et al. (2018) Cellular senescence in intervertebral disc aging and degeneration. Curr Mol Biol Rep 4:180-190|
|Robinson, Andria R; Yousefzadeh, Matthew J; Rozgaja, Tania A et al. (2018) Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. Redox Biol 17:259-273|
|Xu, Ming; Pirtskhalava, Tamar; Farr, Joshua N et al. (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24:1246-1256|
|Ngo, Kevin; Patil, Prashanti; McGowan, Sara J et al. (2017) Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype. Mech Ageing Dev 166:16-23|
|Ngo, Kevin; Pohl, Pedro; Wang, Dong et al. (2017) ADAMTS5 Deficiency Protects Mice From Chronic Tobacco Smoking-induced Intervertebral Disc Degeneration. Spine (Phila Pa 1976) 42:1521-1528|
|Vo, Nam V; Hartman, Robert A; Patil, Prashanti R et al. (2016) Molecular mechanisms of biological aging in intervertebral discs. J Orthop Res 34:1289-306|
|Pohl, Pedro H I; Lozito, Thomas P; Cuperman, Thais et al. (2016) Catabolic effects of endothelial cell-derived microparticles on disc cells: Implications in intervertebral disc neovascularization and degeneration. J Orthop Res 34:1466-74|