Small Molecule Inhibitor Of Bone Morphogenetic Protein Signaling (ldn-193189) Leads To Diminished Bone And Muscle Volume Following Burn Plus Tenotomy
Jacob R. Rinkinen, MD, Shailesh Agarwal, MD, Charles Hwang, BA, Jonathan Peterson, BS, Shawn Loder, BS, John Li, MD, Shuli Li, MD, PhD, Stewart Wang, MD, PhD, Paul Cederna, MD, Benjamin Levi, MD.
University of Michigan, Ann Arbor, MI, USA.
BMP receptor inhibitor LDN-193189 has great promise for treatment of genetic and traumatic causes of heterotopic ossification, hereditary hemorrhagic telangiectasia, and fibrodysplasia ossificans progressive. Despite BMP signaling inhibitor’s utility, kinase inhibitors can be non-specific and cause off target effects. In this article we set out to determine if therapeutic levels of LDN induces off target effects in a trauma/burn injury model.
In vivo studies were performed on C57/BL6 mice using an Achillies tenotomy with concurrent burn injury model. μCT analysis was performed at 5 and 9 weeks following injury to quantify bone and muscle characteristics. The global impact of LDN treatment on SMAD and non-SMAD signaling was assessed using western blot, immunohistochemistry (IHC), and immunofluorescence (IF) of the hind limb skeletal muscle.
Here we noted a reduction in bone volume at 9 weeks in the control non-tenotomy leg. Similarly, a significant decrease in muscle volume was seen at 5 weeks in the tenotomy leg of LDN treated mice compared to non-LDN treated mice. The decline in bone and muscle volume correlated with a reduction in P-SMAD 1/5/9, P-ERK 1/2, and VEGF-A, and increase in p-NFκB protein expression (Fig. 1). LDN
We demonstrate that BMP receptor kinase inhibitor LDN blocks both SMAD and non-SMAD signaling and shows distinct off target effects on muscle and bone volume. These findings point to potential unwarranted off target effects of using BMP inhibitors following trauma/thermal injury. Clinicians should be aware of these potential side effects when using BMP signaling inhibitors.
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