Figure 7 Inhibition of protein palmitoylation compromised p38 MAPK.A. 2BP showed an inhibitory effect on p38 MAPK activation in differentiation assays, without a significant effect on Erk1/2 activation or Smad1/5/8 activation. Primary osteoblasts were cultured in differentiation medium with or without 2BP for different periods of time. Cells were collected for Western blot analysis of the activation of p38, Erk1/2, and Smad1/5/8. B. 2BP also compromised p38 MAPK activation in response to BMP2. Primary osteoblasts were pretreated with PAT inhibitor overnight, and then stimulated with 100 ng/ml of BMP2. Cells were collected at different time points for analysis of p38 and Erk1/2 activation..
Protein Palmitoylation Regulates Osteoblast Differentiation through BMP Induced Osterix Expression
PLoS ONE. 2009 Jan 6; 4(1):e4135
Osteoporosis is one of the most common diseases and can be treated by either anti resorption drugs, anabolic drugs, or both. To search for anabolic dr.....
Osteoporosis is one of the most common diseases and can be treated by either anti resorption drugs, anabolic drugs, or both. To search for anabolic drug targets for osteoporosis therapy, it is crucial to understand the biology of bone forming cells, osteoblasts, in terms of their proliferation, differentiation, and function. Here we found that protein palmitoylation participates in signaling pathways that control osterix expression and osteoblast differentiation. Mouse calvarial osteoblasts express most of the 24 palmitoyl transferases, with some being up regulated during differentiation. Inhibition of protein palmitoylation, with a substrate analog inhibitor, diminished osteoblast differentiation and mineralization, but not proliferation or survival. The decrease in differentiation capacity is associated with a reduction in osterix, but not Runx2 or Atf4. Inhibition of palmitoyl transferases had little effect in p53 / osteoblasts that show accelerated differentiation due to overexpression of osterix, suggesting that osterix, at least partially, mediated the effect of inhibition of palmitoyl transferases on osteoblast differentiation. BMPs are the major driving force of osteoblast differentiation in the differentiation assays. We found that inhibition of palmitoyl transferases also compromised BMP2 induced osteoblast differentiation through down regulating osterix induction. However, palmitoyl transferases inhibitor did not inhibit Smad1/5/8 activation. Instead, it compromised the activation of p38 MAPK, which are known positive regulators of osterix expression and differentiation. These results indicate that protein palmitoylation plays an important role in BMP induced MAPK activation, osterix expression, and osteoblast differentiation.
Leong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.