RESUMO
During the aging process, the reduced osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) results in decreased bone formation, which contributes to senile osteoporosis. Previous studies have confirmed that interrupted circadian rhythm plays an indispensable role in age-related disease. However, the mechanism underlying the impaired osteogenic differentiation of BM-MSCs during aging and its relationship with interrupted circadian rhythm remains unclear. In this study, we confirmed that the circadian rhythm was interrupted in aging mouse skeletal systems. The level of the core rhythm component BMAL1 but not that of CLOCK in the osteoblast lineage was decreased in senile osteoporotic specimens from both human and mouse. BMAL1 targeted TTK as a circadian-controlled gene to phosphorylate MDM2 and regulate H2Bub1 level, while H2Bub1 in turn regulated the expression of BMAL1. The osteogenic capacity of BM-MSCs was maintained by a positive loop formed by BMAL1-TTK-MDM2-H2Bub1. Furthermore, we demonstrated that using bone-targeting recombinant adeno-associated virus 9 (rAAV9) to enhance Bmal1 or Ttk might have a therapeutic effect on senile osteoporosis and delays bone repair in aging mice. In summary, our study indicated that targeting the BMAL1-TTK-MDM2-H2Bub1 axis via bone-targeting rAAV9 might be a promising strategy for the treatment of senile osteoporosis.
RESUMO
BACKGROUND: Studies have shown that lumbar disc herniation, degenerative lumbar instability, and other degenerative lumbar spinal diseases are often secondary to disc degeneration. By studying the intervertebral disc, researchers have clarified the pathological changes involved in intervertebral disc degeneration but have ignored the roles of biomechanical factors in the development of disc degeneration. This study aims to investigate the relationships among the location, scope, and extent of lumbar disc degeneration and sagittal spinal-pelvic parameters. METHODS: A retrospective analysis was performed on the clinical data of 284 patients with lumbar degenerative disc diseases (lumbar disc herniation and degenerative lumbar instability) from January 2013 to December 2016. Statistics were calculated for the following: (1.) patients' general information: name, sex, age, height, and weight. (2.) Measurements of sagittal parameters from total spinal radiographs: thoracic kyphosis (TK), Lumbar lordosis (LL), sacral slope (SS), pelvic tilt (PT), pelvic incidence (PI), sagittal vertical axis (SVA), T1 tilt angle (TA), and T1 pelvic angle (TPA). (3.) Location, scope, extent, and overall degree of lumbar disc degeneration. Parameters were analyzed in groups by sex, PI, and SVA, and a correlation analysis was performed for the location, scope, extent, and overall degree of lumbar intervertebral disc degeneration with 8 spinal-pelvic sagittal parameters. RESULTS: The mean ages of the male and female patient groups were 59.00 and 53.28 years old, respectively (P < 0.05). The PT, location, scope, and overall degree of degradation were significantly different between the sexes (P < 0.05). Linear correlation analysis results showed that the overall degree and extent of degradation (r = 0.788, P < 0.01), LL and SS (r = 0.737, P < 0.01), PI and PT (r = 0.607, P < 0.01), and TPA and PT (r = 0.899, P < 0.01) were strongly correlated. The location values were 4.08 ± 0.72 in patients with PI≤50° and 3.62 ± 0.94 in patients with PI> 50° (P = 0.018). Different SVASVA groups differed in their overall degree of degeneration (P = 0.002). CONCLUSIONS: The location of lumbar intervertebral disc degeneration is affected by spinal-pelvic sagittal morphology. Populations with small PI values tend to exhibit degeneration at the L4/5 and L5/S1 discs, and populations with large PI values tend to exhibit degeneration at the L3/4 and L4/5 discs. The SVA value and the overall degree of lumbar disc degeneration are positively correlated.
