Age-associated callus senescent cells produce TGF-β1 that inhibits fracture healing in aged mice.
The Journal of clinical investigation
Cellular senescence plays an important role in human diseases, including osteoporosis and osteoarthritis. Senescent cells (SCs) produce the senescence-associated secretory phenotype to affect the function of neighboring cells and SCs themselves. Delayed fracture healing is common in the elderly and is accompanied by reduced mesenchymal progenitor cells (MPCs). However, the contribution of cellular senescence to fracture healing in the aged has not to our knowledge been studied. Here, we used C57BL/6J 4-month-old young and 20-month-old aged mice and demonstrated a rapid increase in SCs in the fracture callus of aged mice. The senolytic drugs dasatinib plus quercetin enhanced fracture healing in aged mice. Aged callus SCs inhibited the growth and proliferation of callus-derived MPCs (CaMPCs) and expressed high levels of TGF-β1. TGF-β-neutralizing Ab prevented the inhibitory effects of aged callus SCs on CaMPCs and promoted fracture healing in aged mice, which was associated with increased CaMPCs and proliferating cells. Thus, fracture triggered a significant cellular senescence in the callus cells of aged mice, which inhibited MPCs by expressing TGF-β1. Short-term administration of dasatinib plus quercetin depleted callus SCs and accelerated fracture healing in aged mice. Senolytic drugs represent a promising therapy, while TGF-β1 signaling is a molecular mechanism for fractures in the elderly via SCs.
Short-term senolytic treatment: a paradigm to promote fracture repair during aging.
The Journal of clinical investigation
Increased age is blamed for a wide range of bone physiological changes, and although the underlying mechanisms affecting the decreased capacity for fracture healing are not fully understood, they are clearly linked to changes at the cellular level. Recent evidence suggests potential roles of senescent cells in response to most tissue injuries, including bone fractures. In this issue of the JCI, Liu, Zhang, and co-authors showed that a senolytic drug cocktail cleared senescent cells from the callus and improved bone fracture repair in aged mice. Understanding how senescent cells emerge at fracture sites and how their timely removal improves fracture healing should provide insights for effective therapeutic approaches in old age.
Muscle density is an independent risk factor of second hip fracture: a prospective cohort study.
Journal of cachexia, sarcopenia and muscle
BACKGROUND:Patients with a first hip fracture are at high risk of fracturing their other hip. Despite this, preventive therapy is often not given. Because little is known about specific risk factors of a second hip fracture, we investigated the association with areal bone mineral density (aBMD), muscle size, and density. We also investigated whether muscle parameters predict the risk of a contralateral fracture independently of aBMD. METHODS:Three groups were included, one without hip fracture (a subcohort of the China Action on Spine and Hip Status study), one with a first, and one with a second hip fracture. Subjects with fractures were recruited from the longitudinal Chinese Second Hip Fracture Evaluation (CSHFE). Computed tomography scans of CSHFE patients, which were obtained immediately following their first fracture, were used to measure cross-sectional area and density of the gluteus maximus (G.MaxM) and gluteus medius and minimus (G.Med/MinM) muscles. Computed tomography X-ray absorptiometry was used to measure aBMD of the contralateral femur. Median follow-up time to second fracture was 4.5 years. Cox proportional hazards models were used to compute hazard ratios (HR) of second hip fracture risk in subjects with a first hip fracture. Multivariate logistic regressions were used to compare odds ratios (OR) for the risk of a first and second hip fracture. RESULTS:Three hundred and one participants (68.4 ± 6.1 years, 64% female) without and 302 participants (74.6 ± 9.9 years, 71% female) with a first hip fracture were included in the analysis. Among the latter, 45 (79.2 ± 7.1 years) sustained a second hip fracture. ORs for first hip fracture were significant for aBMD and muscle size and density. ORs for a second fracture were smaller by a factor of 3 to 4 and no longer significant for femoral neck (FN) aBMD. HRs for predicting second hip fracture confirmed the results. G.Med/MinM density (HR, 1.68; CI, 1.20-2.35) and intertrochanter aBMD (HR, 1.62; CI, 1.13-2.31) were the most significant. FN aBMD was not significant. G.Med/MinM density remained significant for predicting second hip fracture after adjustment for FN (HR, 1.66; Cl, 1.18-2.30) or total hip aBMD (HR, 1.50; 95% Cl, 1.04-2.15). CONCLUSIONS:Density of the G.Med/MinM muscle is an aBMD independent predictor of the risk of second hip fracture. Intertrochanteric aBMD is a better predictor of second hip fracture than FN and total hip aBMD. These results may trigger a paradigm shift in the assessment of second hip fracture risk and prevention strategies.