Activation of mTORC1 in subchondral bone preosteoblasts promotes osteoarthritis by stimulating bone sclerosis and secretion of CXCL12

Bone Research
Chuangxin LinXiaochun Bai

Abstract

Increasing evidences show that aberrant subchondral bone remodeling plays an important role in the development of osteoarthritis (OA). However, how subchondral bone formation is activated and the mechanism by which increased subchondral bone turnover promotes cartilage degeneration during OA remains unclear. Here, we show that the mechanistic target of rapamycin complex 1 (mTORC1) pathway is activated in subchondral bone preosteoblasts (Osterix+) from OA patients and mice. Constitutive activation of mTORC1 in preosteoblasts by deletion of the mTORC1 upstream inhibitor, tuberous sclerosis 1, induced aberrant subchondral bone formation, and sclerosis with little-to-no effects on articular cartilage integrity, but accelerated post-traumatic OA development in mice. In contrast, inhibition of mTORC1 in preosteoblasts by disruption of Raptor (mTORC1-specific component) reduced subchondral bone formation and cartilage degeneration, and attenuated post-traumatic OA in mice. Mechanistically, mTORC1 activation promoted preosteoblast expansion and Cxcl12 secretion, which induced subchondral bone remodeling and cartilage degeneration during OA. A Cxcl12-neutralizing antibody reduced cartilage degeneration and alleviated OA in mice. Altoget...Continue Reading

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Citations

Sep 25, 2019·International Journal of Molecular Sciences·Béla KovácsElőd Ernő Nagy
Mar 8, 2019·Nature Reviews. Rheumatology·Jessica McHugh
Jul 1, 2020·Bone Research·Zhenhong NiLin Chen
Feb 9, 2021·Frontiers in Cell and Developmental Biology·Xiaobo ZhuYangzi Jiang
Sep 12, 2020·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Kai LiZhipeng Zou
Feb 23, 2020·Osteoarthritis and Cartilage·K SunF Guo
Jun 20, 2021·Bone Research·Zhenhong NiLin Chen
Jan 21, 2022·Journal of Dental Research·J LeiY Chai

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Datasets Mentioned

BETA
GSE74781

Methods Mentioned

BETA
PCR
ELISA
genotyping
transgenic
chip
electrophoresis

Software Mentioned

GraphPad
OsteoMeasure XP
GraphPad Prism

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