Long-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice.

Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. Due to the link between disc degeneration and senescence, we explored the ability of the Dasatinib and Quercetin drug combination (D + Q) to prevent an age-dependent progression of disc degeneration in mice. We treated C57BL/6 mice beginning at 6, 14, and 18 months of age, and analyzed them at 23 months of age. Interestingly, 6- and 14-month D + Q cohorts show lower incidences of degeneration, and the treatment results in a significant decrease in senescence markers p16INK4a, p19ARF, and SASP molecules IL-6 and MMP13. Treatment also preserves cell viability, phenotype, and matrix content. Although transcriptomic analysis shows disc compartment-specific effects of the treatment, cell death and cytokine response pathways are commonly modulated across tissue types. Results suggest that senolytics may provide an attractive strategy to mitigating age-dependent disc degeneration.

Comparison of inbred mouse strains shows diverse phenotypic outcomes of intervertebral disc aging.

Intervertebral disc degeneration presents a wide spectrum of clinically degenerative disc phenotypes; however, the contribution of genetic background to the degenerative outcomes has not been established. We characterized the spinal phenotype of 3 mouse strains with varying cartilage-regenerative potential at 6 and 23 months: C57BL/6, LG/J and SM/J. All strains showed different aging phenotypes. Importantly, LG/J mice showed an increased prevalence of dystrophic disc calcification in caudal discs with aging. Quantitative-histological analyses of LG/J and SM/J caudal discs evidenced accelerated degeneration compared to BL6, with cellular disorganization and cell loss together with fibrosis of the NP, respectively. Along with the higher grades of disc degeneration, SM/J, at 6M, also differed the most in terms of NP gene expression compared to other strains. Moreover, although we found common DEGs between BL6 and LG/J aging, most of them were divergent between the strains. Noteworthy, the common DEGs altered in both LG/J and BL6 aging were associated with inflammatory processes, response to stress, cell differentiation, cell metabolism and cell division. Results suggested that disc calcification in LG/J resulted from a dystrophic calcification process likely aggravated by cell death, matrix remodelling, changes in calcium/phosphate homeostasis and cell transformation. Lastly, we report 7 distinct phenotypes of human disc degeneration based on transcriptomic profiles, that presented similar pathways and DEGs found in aging mouse strains. Together, our results suggest that disc aging and degeneration depends on the genetic background and involves changes in various molecular pathways, which might help to explain the diverse phenotypes seen during disc disease.

TonEBP-deficiency accelerates intervertebral disc degeneration underscored by matrix remodeling, cytoskeletal rearrangements, and changes in proinflammatory gene expression.

The tonicity-responsive enhancer binding protein (TonEBP) plays an important role in intervertebral disc and axial skeleton embryogenesis. However, the contribution of this osmoregulatory transcription factor in postnatal intervertebral disc homeostasis is not known in vivo. Here, we show for the first time that TonEBP-deficient mice have pronounced age-related degeneration of the intervertebral disc with annular and endplate herniations. Using FTIR-imaging spectroscopy, quantitative immunohistochemistry, and tissue-specific transcriptomic analysis, we provide morphological and molecular evidence that the overall phenotype is driven by a replacement of water-binding proteoglycans with fibrocartilaginous matrix. Whereas TonEBP deficiency in the AF compartment caused tissue fibrosis associated with alterations in actin cytoskeleton and adhesion molecules, predominant changes in pro-inflammatory pathways were seen in the NP compartment of mutants, underscoring disc compartment-specific effects. Additionally, TonEBP-deficient mice presented with compromised trabecular bone properties of vertebrae. These results provide the first in vivo support to the long-held hypothesis that TonEBP is crucial for postnatal homeostasis of the spine and controls a multitude of functions in addition to cellular osmoadaptation.

Home Visits for Children and Adolescents with Uncontrolled Type 1 Diabetes.

Background: Home-based video visits were provided over one year as a supplement to in-person care for pediatric type 1 diabetes (T1D) patients with suboptimal glycemic control. We hypothesized that the intervention would be feasible and satisfactory for the target population and would significantly improve hemoglobin A1c (HbA1c) levels and completion of recommended quarterly diabetes clinic visits. Methods: This was a nonrandomized clinical trial. Fifty-seven patients aged 3-17 years with known T1D and HbA1c ≥8% (64 mmol/mol) were recruited to receive the intervention. The study population was 49% adolescent (13-17 years old) and 58% publicly insured patients. Video visits were scheduled every 4, 6, or 8 weeks depending on the HbA1c level. HbA1c levels as well as frequencies of clinic visits and of diabetes-related emergency department (ED) and hospital encounters were compared before and after the study. Results: Thirty participants completed 12 months of video visits. The study cohort demonstrated significant improvement in mean HbA1c in both intention-to-treat (N = 57) analysis (10.8% [95 mmol/mol] to 10.0% [86 mmol/mol], P = 0.01) and per-protocol (N = 30) analysis (10.8% [95 mmol/mol] to 9.6% [81 mmol/mol], P = 0.004). Completion of ≥4 annual diabetes clinic visits improved significantly from 21% at baseline to 83% during the study period for the entire cohort, P < 0.0001. The frequency of diabetes-related ED and hospital encounters did not change significantly. Conclusions: Home-based video visits are a feasible supplement to in-person care for children and adolescents with T1D and suboptimal glycemic control and can successfully improve HbA1c levels and adherence to recommended frequency of care in this high-risk clinical population.