Long-term use of fluoxetine accelerates bone loss through the disruption of sphingolipids metabolism in bone marrow adipose tissue.
Transl Psychiatry
; 10(1): 138, 2020 05 12.
Article
em En
| MEDLINE
| ID: mdl-32398744
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Medula Óssea
/
Transtorno Depressivo Maior
Idioma:
En
Revista:
Transl Psychiatry
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China