Long-term use of fluoxetine accelerates bone loss through the disruption of sphingolipids metabolism in bone marrow adipose tissue

Huili Zhang, Kefeng Li, Yanna Zhao, Yilan Zhang, Jiawen Sun, Shihong Li, Guangwu Lin

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Fluoxetine is a commonly prescribed antidepressant, and the mechanisms of increased bone fragility with its long-term use remain largely unknown. Here, we show that long-term administration of fluoxetine induces the disruption of sphingolipids metabolism in bone marrow adipose tissue (BMAT)through the inhibition of acid sphingomyelinase (ASM). Similarly, a significant reduction of the bone volume was observed in mice with ASM knockout (Smpd1−/−). In detail, inhibition of ASM by fluoxetine reduces the sphingosine-1-phosphate (S1P) level in bone marrow adipocytes, leading to the increase of receptor activator of nuclear factor-kappa-Β ligand (RANKL) secretion, a key regulator for the activation of osteoclastogenesis and bone loss, through the upregulation of cyclooxygenase-2 and its enzymatic product prostaglandin E2 (COX-2/PGE2). In contrast, overexpression of ASM by cisplatin normalizes fluoxetine-induced RANKL overproduction. Furthermore, we conducted a clinical trial with L-serine, a precursor of sphingolipids biosynthesis. The results show that oral supplementation of L-serine (250 mg//kg/d) prevents the acceleration of bone loss caused by long-term fluoxetine (12 months) in postmenopausal women with major depressive disorder (mean total hip bone mineral density reduction: −2.0% vs −1.1%, P = 0.006). Our study provides new insights and potential treatment strategy on the bone loss caused by long-term use of fluoxetine.

Original languageEnglish
Article number138
JournalTranslational Psychiatry
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2020
Externally publishedYes

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