Chronic Psychological Stress Impairs Bone Metabolism by Downregulating miR-335-3p and Promoting Osteoclast Activity

Concepts de base

Chronic psychological stress leads to bone loss by downregulating miR-335-3p, which normally inhibits osteoclast activity by targeting Fos, thereby promoting the NFATC1 signaling pathway and accelerating osteoclast differentiation and maturation.

Résumé

This study investigated the mechanism by which chronic psychological stress leads to osteoporosis. The researchers established a chronic unpredictable mild stress (CUMS) mouse model and found that these mice exhibited an osteoporosis phenotype, which was mainly attributed to abnormal osteoclast activity rather than decreased osteoblast function.
Through miRNA sequencing and analysis, the researchers identified miR-335-3p as a key regulator that was significantly downregulated in the nucleus ambiguous (NAC), serum, and bone tissue of CUMS mice. Further in vitro studies showed that miR-335-3p directly targets the Fos gene, which is a critical transcription factor for osteoclast differentiation and activation.
The downregulation of miR-335-3p under chronic stress led to increased Fos expression and enhanced NFATC1 signaling in osteoclasts, ultimately accelerating their differentiation and maturation. This resulted in elevated osteoclast activity and bone loss in the CUMS mice.
The study provides new insights into the central-peripheral communication mechanisms by which psychological stress affects bone metabolism. It suggests that miR-335-3p is an important regulator linking the brain and bone, and its downregulation under chronic stress is a key driver of stress-induced osteoporosis. These findings highlight the potential of miR-335-3p as a therapeutic target for treating psychological stress-related bone disorders.

Stats

Chronic unpredictable mild stress (CUMS) led to a significant decrease in body weight of mice compared to control.
CUMS mice exhibited anxiety- and depression-like behaviors, including reduced distance and time spent in the central area of the open field test, increased immobility time in the tail suspension test, and decreased sucrose preference.
Serum corticosterone and norepinephrine levels were significantly elevated in CUMS mice.
Micro-CT analysis showed that CUMS mice had reduced trabecular and cortical bone mass in the femur compared to control mice.
TRAP staining and qRT-PCR analysis revealed that osteoclast activity and osteoclast-related gene expression were significantly increased in the femurs of CUMS mice.

Citations

"Our findings show that the abnormal osteoclast activity is much more responsible for the psychological stress induced osteoporosis."
"miR-335-3p plays an important role in the communication between central nervous system and peripheral bone tissue, in addition, provide a new perspective on neuroregulatory mechanisms of the brain that participated in bone metabolism when suffering psychological stress."

Idées clés tirées de

Psychological stress disturbs bone metabolism via miR-335-3p/Fos signaling in osteoclast

by Zhang,J., Li... à www.biorxiv.org 02-23-2024

https://www.biorxiv.org/content/10.1101/2024.02.20.581167v1

Questions plus approfondies

How might the downregulation of miR-335-3p in the brain under chronic stress be targeted therapeutically to prevent the negative effects on bone metabolism?

The downregulation of miR-335-3p in the brain under chronic stress can be targeted therapeutically through various approaches. One potential strategy is to develop miRNA-based therapies that aim to restore the levels of miR-335-3p in the brain. This can be achieved by delivering exogenous miR-335-3p mimics to the brain, either through direct injection or using nanoparticle-based delivery systems. By increasing the levels of miR-335-3p, the inhibitory effect on Fos expression can be restored, thereby reducing the activation of the NFATC1 signaling pathway in osteoclasts. This approach could help prevent the accelerated osteoclast differentiation and abnormal bone metabolism associated with chronic stress-induced osteoporosis.

What other brain-derived miRNAs or signaling pathways could be involved in the central regulation of bone homeostasis, and how do they interact with the miR-335-3p/Fos axis?

Several other brain-derived miRNAs and signaling pathways may also play a role in the central regulation of bone homeostasis. For example, miR-483-5p, which is stored in brain-derived extracellular vesicles, has been shown to promote bone-fat imbalance in Alzheimer's disease. These miRNAs could potentially interact with the miR-335-3p/Fos axis by targeting different components of the osteoclast differentiation pathway or by modulating the expression of key regulatory genes involved in bone metabolism. Additionally, signaling pathways such as the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, which are known to be activated during stress, could also influence bone homeostasis through their effects on miRNA expression and downstream signaling cascades.

Given the broad biological functions of miR-335-3p, what are the potential side effects or unintended consequences of targeting this miRNA for the treatment of stress-induced osteoporosis, and how could these be mitigated?

While targeting miR-335-3p for the treatment of stress-induced osteoporosis holds promise, there are potential side effects and unintended consequences that need to be considered. One possible concern is off-target effects, where the exogenous miR-335-3p mimics may inadvertently interfere with the expression of other genes or pathways, leading to unforeseen physiological effects. To mitigate this risk, thorough preclinical studies should be conducted to assess the specificity and safety of the miRNA-based therapy. Additionally, the dosing and delivery methods of the miR-335-3p mimics should be carefully optimized to minimize potential off-target effects.
Another consideration is the potential for immune responses or inflammatory reactions to the exogenous miRNA mimics. To address this, the development of delivery systems that enhance the stability and bioavailability of the miRNA mimics, while minimizing immune activation, could help mitigate these risks. Furthermore, close monitoring of patients undergoing miRNA-based therapy for stress-induced osteoporosis is essential to promptly identify and address any adverse effects that may arise.