Nicotinamide inhibits Heterotopic ossification decreasing Smad 1/5/8 phosphorylation

Heterotopic ossification (HO) is a condition in wich extra-skeletal bone formation occurs in soft tissues of the body. HO is formed in numerous clinical situations such as burns, neurological damage, post-combat trauma, hip surgery, etc. The most severe condition of heterotopic ossification is the pathology called Fibrodysplasia Ossificans Progressiva (FOP), wich is produced by a point mutation in the ACVR1 receptor gene, triggering its constitutive activation and a hyper-activation of the SMAD pathway. Different pharmacological treatments have been used to inhibit the progression of ossification outbreaks, but a low effectiveness has been reported. An alternative therapy is the use of nicotinamide where a delay in the appearance of ossification flare ups has been observed. However, its effect on the SMAD-mediated signaling pathway is not known. In this work we use nicotinamide in culture of C2C12 cells in the presence or absence of the osteoinductive BMP-2 to investigate its effect on osteoblastogenesis. Through western blot, Inmmunocytochemistry and Real time PCR we investigated the effect of nicotinamide on the SMAD pathway and gene expression of genes involved in the pathology. Our results show that in the presence of nicotinamide a decrease in the osteoblast differentiation and in SMAD complex phosphorylation levels while expression of the ACVR1 BMP-2 receptor and Runx2 are not affected by the treatment. New evidence is provided regarding the mechanism by which nicotinamide acts. These findings could be helpful in the clinic for the treatment of diseases related to HO bone formation.