Calcium-mediated Stress Kinase Activation by DMP1 Promotes Osteoblast Differentiation

• Published in: The Journal of biological chemistry 2010-11, Vol.285 (47), p.36339-36351
• Main Authors: Eapen, Asha, Sundivakkam, Premanand, Song, Yiqiang, Ravindran, Sriram, Ramachandran, Amsaveni, Tiruppathi, Chinnaswammy, George, Anne
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Bone; Calcium - metabolism; Cell Differentiation; Cells, Cultured; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Fluorescent Antibody Technique; Gene Regulation; Heat Shock Protein; Heat-Shock Proteins - antagonists & inhibitors; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Integrins - antagonists & inhibitors; Integrins - genetics; Integrins - metabolism; MAPKs; Mice; Mice, Inbred C3H; Osteoblasts - cytology; Osteoblasts - metabolism; p38 MAPK; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction; Skull - cytology; Skull - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.145607

Calcium signaling and calcium transport play a key role during osteoblast differentiation and bone formation. Here, we demonstrate that DMP1 mediated calcium signaling, and its downstream effectors play an essential role in the differentiation of preosteoblasts to fully functional osteoblasts. DMP1, a key regulatory bone matrix protein, can be endocytosed by preosteoblasts, triggering a rise in cytosolic levels of calcium that initiates a series of downstream events leading to cellular stress. These events include release of store-operated calcium that facilitates the activation of stress-induced p38 MAPK leading to osteoblast differentiation. However, chelation of intracellular calcium and inhibition of the p38 signaling pathway by specific pharmacological inhibitors and dominant negative plasmid suppressed this activation. Interestingly, activated p38 MAPK can translocate to the nucleus to phosphorylate transcription factors that coordinate the expression of downstream target genes such as Runx 2, a key modulator of osteoblast differentiation. These studies suggest a novel paradigm by which DMP1-mediated release of intracellular calcium activates p38 MAPK signaling cascade to regulate gene expression and osteoblast differentiation.