Clomipramine causes osteoporosis by promoting osteoclastogenesis via E3 ligase Itch, which is prevented by Zoledronic acid

Abstract

Patients taking antidepressants, including Clomipramine (CLP), have an increased risk of osteoporotic fracture. However, the effects of CLP on bone metabolism are unknown. Here, we demonstrate that WT mice treated with CLP for 2 weeks had significantly reduced trabecular bone volume and cortical bone thickness, associated with increased osteoclast (OC) numbers, but had no change in osteoblast numbers or bone formation rate. Bone marrow cells from CLP-treated mice had normal OC precursor frequency, but formed significantly more OCs when they were cultured with RANKL and M-CSF. CLP promoted OC formation and bone resorption and expression of OC-associated genes. CLP-induced bone loss was prevented by Zoledronic acid. At the molecular level, CLP inhibited the activity of the ubiquitin E3 ligase Itch. CLP did not promote OC formation from bone marrow cells of Itch−/− mice in vitro nor induce bone loss in Itch−/− mice. Our findings indicate that CLP causes bone loss by enhancing Itch-mediated osteoclastogenesis, which was prevented by Zoledronic acid. Thus, anti-resorptive therapy could be used to prevent bone loss in patients taking antidepressants, such as CLP.

Targeting Bortezomib to Bone Increases Its Bone Anabolic Activity and Reduces Systemic Adverse Effects in Mice

“…Adjacent sections were also stained for TRAP activity to identify OCs. Histomorphometric analyses were performed on sections cut at three levels in each sample using CMSR SOPs . In brief, stained sections were numbered blindly and were converted to digital images using an Olympus VS120 whole slide imaging system (Olympus, Center Valley, PA, USA).…”

“…Histomorphometric analyses were performed on sections cut at three levels in each sample using CMSR SOPs. (36,37) In brief, stained sections were numbered blindly and were converted to digital images using an Olympus VS120 whole slide imaging system (Olympus, Center Valley, PA, USA). A full static bone histomorphometric analysis in long bone, including BV/TV (%), Tb.Th (μm), Tb.N (/mm), Tb.Sp (mm), osteoblast surface/bone surface (Ob.S/BS; %), osteoclast surface/bone surface (Oc.S/BS; %), and eroded surface/bone surface (ES/BS; %), were performed in the secondary spongiosa area using the automated algorithm with a Visiopharm Image Analysis System as we previously described.…”

Synthesis of a Bone-Targeted Bortezomib with In Vivo Anti-Myeloma Effects in Mice

“…Histomorphometric analyses were performed on sections cut at 3 representative levels in each bone. The percentage of trabecular bone (BV/TV) was analyzed using the automated algorithm we developed with the Visiopharm Image Analysis System [ 14 ]. (2) The frozen sections (8 μm) were cut using a Leica CM1850 cryostat (Leica, German) and mounted with a mounting medium containing DAPI (Vector Lab., Burlingame, CA, USA).…”

Various pathways of zoledronic acid against osteoclasts and bone cancer metastasis: a brief review

“…Many experiments have demonstrated that ZA inhibits bone destruction caused by enhanced differentiation and function of osteoclasts by interrupting RANKL/RANK pathway [ 17 , 18 , 38 ] (Fig. 1 ).…”

“…ZA decreases the expression of RANK to inhibit the differentiation of osteoclasts through suppressing TNF-α and RANKL [ 39 – 41 ]. In addition, it is reported that ZA also inhibits NFATc1 and c-fos [ 17 , 26 , 42 ], suppresses NF-κB pathway through promoting the deubiquitination of TRAF6 [ 18 ], as well as the phosphorylation of tyrosine and the nuclear translocation of p65 [ 43 ].

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