Site-specific regulation of bone strength for the prevention of osteoporotic fractures
| Reference number | |
| Coordinator | Göteborgs Universitet - KLINFARM LAB |
| Funding from Vinnova | SEK 453 255 |
| Project duration | June 2017 - January 2018 |
| Status | Completed |
Purpose and goal
Palmitoleoylation of WNTs by the enzyme Porcupine is essential for WNTs cell trafficking and signaling through the binding to Frizzled receptors. NOTUM is an extracellular WNT lipase, removing palmitoleic acid from WNT and thereby abolishes its activity. The aim of this study was to evaluate the role of Porcupine-mediated palmitoleoylation of WNTs for trabecular and cortical bone mass. As Porcn-/- mice display embryonal lethality, we used Porcupine inhibitors (PORCN_I) to determine the role of Porcupine for bone mass in adult mice.
Expected results and effects
Total body BMD was decreased by PORCN_I while it was increased by NOTUM inhibition. Cortical thickness at the femur was also decreased by PORCN_I and increased by NOTUM inhibition. Vertebral trabecular bone volume fraction was substantially decreased by PORCN_I but unchanged by NOTUM inhibition. In conclusion, palmitoleoylation of WNTs by Porcupine is a major determinant of both trabecular and cortical bone mass. In addition, our findings suggest that Porcupine inhibitors, under development for cancer treatment, may have deleterious skeletal side-effects.
Planned approach and implementation
Twelve-week-old female mice were treated for three weeks by oral gavage with two different PORCN_I (LGK974 at 3 [LGK_Lo] or 6 mg/kg [LGK_Hi] or C59 at 10 mg/kg, Selleckchem), a NOTUM inhibitor (30 mg/kg, Lexicon) or vehicle (n= 10 per group). Bone density was evaluated by DXA (PIXIMUS). Cortical bone was evaluated at the femur by µCT and trabecular bone was evaluated at the spine. Static and dynamic histomorphometry was also performed at the femur and spine. Strength was evaluated at the tibia by the 3-point bending test.