Skip to main content
. Author manuscript; available in PMC: 2017 Mar 5.
Published in final edited form as: Nat Med. 2016 Sep 5;22(10):1170–1179. doi: 10.1038/nm.4166

Figure 6. Co-treatment with propranolol rescues the Flx-induced bone loss.

Figure 6

WT females treated for 6 w with vehicle (veh), Flx, Prop or a combination of both drugs (Flx/Prop). (a) Vertebrae analysis, with representative images (n = 4 images/mouse; scale bars, 400 μm) and quantification of BV/TV (veh n = 8, Flx, Prop and Flx/Prop n = 9) (top) and bone histomorphometric analyses (n = 6 or 8) (bottom). Scale bars, 400 μm. (b) Plasma concentration of OCN. (c) Urine concentration of Dpd crosslinks. Cr, creatinine. (d) Analysis of femurs by microcomputed tomography. Tb.N, trabecular number. Tb.Sp, trabecular spacing. BMD, bone mineral density (veh and Prop n = 10, Flx and Flx/Prop n = 9). Scale bars, 400 μm. (e) Tnfrsf11b and Tnfsf11 expression and Tnfrsf11b/Tnfsf11 ratio in long bones. (f) Urine E and (g) NE concentration. (h) Marble burying test. Values are mean ± SEM. In all panels, (†) represents Flx vs. Flx/Prop groups, (*) represents veh vs. Flx groups. †/*P ≤ 0.05, ††/**P ≤ 0.01, ††††/****P ≤ 0.0001 using Student’s tests. (i) Schematic diagram of Flx mechanism of action on bone remodeling. Flx directly acts on osteoclasts to limit the Ca2+/calmodulin-dependent activation of the c-Fos-Nfatc1 cascade causing a decrease in bone resorption ➀, independently of 5HTT. Also, through its inhibition of serotonin reuptake by 5HTT, Flx increases brain serotonin post-synaptic signaling causing the desensitization of Htr2c ➁. As a result, sympathetic output increases, bone resorption increases and bone formation decreases. Upon a short exposure to fluoxetine the direct effect ➀ is predominant causing an increase in bone mass by decreasing bone resorption. Following a longer treatment, direct ➀ and central ➁ effects counteract each other in term of bone resorption while bone formation decreases, causing bone loss. The deleterious central effect of fluoxetine ➁ on bone remodeling can be prevented by a co-treatment with propranolol, which blocks the increase in Adrb2 signaling in osteoblasts caused by the higher sympathetic tone.

HHS Vulnerability Disclosure