Autophagy receptor OPTN (optineurin) regulates mesenchymal stem cell fate and bone-fat balance during aging by clearing FABP3

Abstract

Senile osteoporosis (OP) is often concomitant with decreased autophagic activity. OPTN (optineurin), a macroautophagy/autophagy (hereinafter referred to as autophagy) receptor, is found to play a pivotal role in selective autophagy, coupling autophagy with bone metabolism. However, its role in osteogenesis is still mysterious. Herein, we identified Optn as a critical molecule of cell fate decision for bone marrow mesenchymal stem cells (MSCs), whose expression decreased in aged mice. Aged mice revealed osteoporotic bone loss, elevated senescence of MSCs, decreased osteogenesis, and enhanced adipogenesis, as well as optn -/mice. Importantly, restoring Optn by transplanting wild-type MSCs to optn -/mice or infecting optn -/mice with Optn-containing lentivirus rescued bone loss. The introduction of a loss-of-function mutant of Optn K193R failed to reestablish a bone-fat balance. We further identified FABP3 (fatty acid binding protein 3, muscle and heart) as a novel selective autophagy substrate of OPTN. FABP3 promoted adipogenesis and inhibited osteogenesis of MSCs. Knockdown of FABP3 alleviated bone loss in optn -/mice and aged mice. Our study revealed that reduced OPTN expression during aging might lead to OP due to a lack of FABP3 degradation via selective autophagy. FABP3 accumulation impaired osteogenesis of MSCs, leading to the occurrence of OP. Thus, reactivating OPTN or inhibiting FABP3 would open a new avenue to treat senile OP.

Scara3 regulates bone marrow mesenchymal stem cell fate switch between osteoblasts and adipocytes by promoting Foxo1

“…For example, the deficiency of TSC1 , a positive inducer of autophagy, resulted in bone loss through suppressing osteogenic differentiation, elevating the osteoclast differentiation and adipogenic differentiation 42 . The autophagy receptor OPTN controlled the cell fate switch between adipocytes and osteoblasts in BMSCs 26 . Here, we validated Scara3 facilitating autophagy.…”

“… 42 The autophagy receptor OPTN controlled the cell fate switch between adipocytes and osteoblasts in BMSCs. 26 Here, we validated Scara3 facilitating autophagy. Further study revealed that the deficiency of Scara3 exacerbated the osteogenesis‐adipogenesis imbalance in BMSCs.…”

“… 21 Moreover, aberrant autophagy could result in the dysfunction of cell fate in BMSCs. 20 , 25 Liu et.al 26 recently showed that autophagy receptor OPTN (optineurin) regulated bone‐fat balance by regulating the cell fate switch. However, it is unclear that if SCARA3 gene is involved in autophagy.…”

Autophagy in major human diseases

“…In a rat model of osteoporosis, reduced levels of autophagy in osteoblasts have been reported (Tang et al, 2019). optn À/À mice show reduced ability to eliminate FABP3 (fatty acid binding protein 3, muscle and heart) by selective autophagy linked to impaired osteogenesis and increased bone loss, thus supporting the notion that decreased expression of OPTN during aging might lead to osteoporosis (Liu et al, 2020c). In contrast, genetic…”

Dynamic Changes of the Bone Marrow Niche: Mesenchymal Stromal Cells and Their Progeny During Aging and Leukemia

“…RANKL, an osteoclastogenic cytokine, has been shown to be increasingly secreted by MSCs in aged mice ( Lin et al, 2017 ), leading to bone loss ( Kim et al, 2020 ). Cellular senescence also leads to a decrease in Optineurin (OPTN), an autophagy receptor therefore contributing to osteoporosis alongside with accumulation of the OPTN substrate fatty acid binding protein 3 (FABP3) ( Liu et al, 2020 ).…”