Journal Article

SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption

Sato, Shingo, Tsuji, Kunikazu, Piao, Jinying, Aobulikasimu, Alkebaier, Ochi, Hiroki, Asou, Yoshinori, Liu, Tao, Okawa, Atsushi

2023

Overview

The mechanistic regulation of bone mass in aged animals is poorly understood. In this study, we examined the role of SIRT6, a longevity-associated factor, in osteocytes, using mice lacking Sirt6 in Dmp-1 -expressing cells (cKO mice) and the MLO-Y4 osteocyte-like cell line. cKO mice exhibited increased osteocytic expression of Sost, Fgf23 and senescence inducing gene Pai-1 and the senescence markers p16 and Il-6 , decreased serum phosphate levels, and low-turnover osteopenia. The cKO phenotype was reversed in mice that were a cross of PAI-1-null mice with cKO mice. Furthermore, senescence induction in MLO-Y4 cells increased the Fgf23 and Sost mRNA expression. Sirt6 knockout and senescence induction increased HIF-1α binding to the Fgf23 enhancer sequence. Bone mass and serum phosphate levels were higher in PAI-1-null aged mice than in wild-type mice. Therefore, SIRT6 agonists or PAI-1 inhibitors may be promising therapeutic options for aging-related bone metabolism disruptions.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/80/304 / 631/80/509 / 692/4023/1671/63 / 692/699/1670/316 / Aging / Animals / Bone mass / Bone turnover / Bones / Cell Line / Fibroblast growth factor 23 / Gene expression / Genotype & phenotype / Humanities and Social Sciences / Hypoxia-inducible factor 1a / Interleukin 6 / Metabolism / Mice / multidisciplinary / Osteocytes / Osteocytes - metabolism / Osteopenia / Osteoporosis / Phenotypes / Phosphates / Phosphates - metabolism / Phosphorus / Plasminogen Activator Inhibitor 1 - genetics / Plasminogen Activator Inhibitor 1 - metabolism / Science / Science (multidisciplinary) / Senescence / Sirtuins - genetics / Sirtuins - metabolism / SOST protein / Therapeutic targets