TAK1 in skeletal homeostasis

Despite evidence that MAPK signaling pathways may be relevant to the development and maintenance of bone and cartilage, their function in osteoblasts and chondrocytes remains poorly characterized. Specifically, we focus on the contribution of Tak1 (MAP3K7) to the development of cartilage and bone. In cartilage, Tak1 functions downstream of BMPs, and mice with a conditional deletion of Tak1 in cartilage display severe runting, growth plate abnormalities, and fusion of the elbow and tarsal joints. Biochemical analysis of TAK1-deficient chondrocytes revealed that TAK1 plays a novel role in amplifying activation of Smads by phosphorylating Smad1 at the same C-terminal serines as the BMP receptor complex. Mice with a conditional deletion of Tak1 in osteoblasts display clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia syndrome seen in humans and mice haploinsufficient for the master osteoblast transcription factor Runx2. Biochemical analysis revealed that TAK1 is required for the phosphorylation and post-translational activation of Runx2 via MKK3/6-p38 MAPK signaling. Confirming that p38 mice with deletions of Mkk3 , Mkk6 , p38α or p38β display reduced bone mass and defective osteoblast differentiation. These findings reveal the only known in vivo function for p38β and provide the first in vivo evidence that the TAK1-MKK3/6-p38 MAPK pathway is a critical regulator of osteoblast differentiation and adult bone mass. Selective p38β agonists may represent novel therapeutics for augmenting bone formation in diseases such as osteoporosis.