c-Jun N-terminal kinases (JNKs) are critical mediators of osteoblast activity in vivo
Program in Molecular Medicine; Division of Rheumatology, Department of Medicine; UMass Metabolic Network; Davis Lab
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
The c-Jun N-terminal kinases (JNKs) are ancient and evolutionarily conserved regulators of proliferation, differentiation and cell death responses. Currently, in vitro studies offer conflicting data about whether the JNK pathway augments or represses osteoblast differentiation, and the contribution of the JNK pathway to regulation of bone mass in vivo remains unclear. Here we show that Jnk1-/- mice display severe osteopenia due to impaired bone formation, whereas Jnk2-/- mice display a mild osteopenia only evident in long bones. In order to both confirm that these effects were osteoblast intrinsic and assess whether redundancy with JNK1 masks a potential contribution of JNK2, mice with a conditional deletion of both JNK1 and JNK2 floxed conditional alleles in osteoblasts (Jnk1-2osx ) were bred. These mice displayed a similar degree of osteopenia to Jnk1-/- mice due to decreased bone formation. In vitro, Jnk1-/- osteoblasts display a selective defect in the late stages of osteoblast differentiation with impaired mineralization activity. Downstream of JNK1, phosphorylation of JUN is impaired in Jnk1-/- osteoblasts. Transcriptome analysis showed that JNK1 is required for upregulation of several osteoblast-derived proangiogenic factors such as IGF2 and VEGFa. Accordingly, JNK1 deletion results in a significant reduction skeletal vasculature in mice. Taken together, this study establishes that JNK1 is a key mediator of osteoblast function in vivo and in vitro.
Angiogenesis, Bone Formation, JNK, JUN, MAPK, Osteoblasts
DOI of Published Version
J Bone Miner Res. 2017 Sep;32(9):1811-1815. doi: 10.1002/jbmr.3184. Link to article on publisher's site
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Xu, Ren; Zhang, Chao; Shin, Dong Yeon; Kim, Jung-Min; Lalani, Sarfaraz; Li, Na; Yang, Yeon-Suk; Liu, Yifang; Eiseman, Mark; Davis, Roger J.; Shim, Jae-Hyuck; and Greenblatt, Matthew B., "c-Jun N-terminal kinases (JNKs) are critical mediators of osteoblast activity in vivo" (2017). UMass Metabolic Network Publications. 109.