The long-term goal of this project is to understand the molecular mechanisms that control biomineralization. We originally identified Dentin matrix protein 1 (DMP1) a noncollagenous protein in odontoblasts and later in osteoblasts. Numerous studies by us and others suggest that DMP1 might play critical roles in the biomineralization process. Recently we discovered that DMP1 can stimulate the release of intracellular calcium in preosteoblasts and preodontoblasts. To refill the ER, plasma membrane Ca 2+ channels need to be activated to permit Ca 2+ entry from the extracellular space. The molecular mechanism by which DMP1 stimulation leads to store depletion and subsequent opening of Ca2+ permeable ion channels namely store-operated calcium channels are not known. Therefore, understanding how DMP1 mediates intracellular calcium release and influx is a new concept. Store operated calcium entry (SOCE) is a principal cellular process by which cells regulate basal Ca2+, refill intracellular Ca2+ and execute a wide range of specialized activities. We also identified two DMP1 interacting proteins, namely, GRP-78 (Glucose-regulated protein- 78) and TRIP-1 (TGF-beta receptor II interacting protein 1). Both GRP-78 and TRIP-1 are ER resident proteins. Thus, the epicenter for DMP1 stimulation is the endoplasmic reticulum. The unifying hypothesis of this proposal is that the release of intracellular Ca2+ by DMP1 stimulation regulates a wide range of cellular functions including osteoblast and odontoblast survival and differentiation. The result wil generate new information that is relevant to understanding molecular mechanisms that control mineralization in bone and dentin. Currently, no channel molecule has been exploited for either therapy or diagnosis of mineralization related disorders. Therefore, the outcomes from this study will help define potential therapeutic targets for bone and dentin repair and regeneration.

Public Health Relevance

Mineralization is a ubiquitous process and is fundamental to human development and health. Dysfunctional mineralization leads to a variety of medical problems and so an understanding of these processes is essential. The proposed studies are designed to understand the function of dentin matrix protein 1 (DMP1) in the biomineralization process. The mechanisms by which DMP1 functions in bone and teeth are poorly understood. The proposed experiments are designed to fill this gap. We identified that DMP1 can cause the release of calcium from intracellular stores. However, the mechanism by which DMP1 stimulation leads to store depletion and subsequent opening of Ca2+ permeable channels are not known. Store operated calcium entry is a key mechanism by which cells convey Ca2+ signals and maintain Ca2+ homeostasis. Dysregulated calcium entry is detrimental to osteoblasts and odontoblasts. We also identified novel DMP1 partners that can perform various functions in matrix mineralization Understanding the mechanism by which intracellular Ca2+ is regulated and identifying the function of DMP1 partners will have important implications in developing novel strategies for bone and dentin repair and regeneration.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wan, Jason
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois at Chicago
Schools of Dentistry/Oral Hygn
United States
Zip Code
Ravindran, Sriram; George, Anne (2014) Multifunctional ECM proteins in bone and teeth. Exp Cell Res 325:148-54
Huang, Chun-Chieh; Ravindran, Sriram; Yin, Ziying et al. (2014) 3-D self-assembling leucine zipper hydrogel with tunable properties for tissue engineering. Biomaterials 35:5316-26
Chandrasekaran, Sangeetha; Ramachandran, Amsaveni; Eapen, Asha et al. (2013) Stimulation of periodontal ligament stem cells by dentin matrix protein 1 activates mitogen-activated protein kinase and osteoblast differentiation. J Periodontol 84:389-95
Bhatia, Ankush; Albazzaz, Michael; Espinoza Orias, Alejandro A et al. (2012) Overexpression of DMP1 accelerates mineralization and alters cortical bone biomechanical properties in vivo. J Mech Behav Biomed Mater 5:1-8
Opsahl Vital, S; Gaucher, C; Bardet, C et al. (2012) Tooth dentin defects reflect genetic disorders affecting bone mineralization. Bone 50:989-97
Alsanea, Rajaa; Ravindran, Sriram; Fayad, Mohamed I et al. (2011) Biomimetic approach to perforation repair using dental pulp stem cells and dentin matrix protein 1. J Endod 37:1092-7
George, Anne; Ravindran, Sriram (2010) PROTEIN TEMPLATES IN HARD TISSUE ENGINEERING. Nano Today 5:254-266
Prescott, Rebecca S; Alsanea, Rajaa; Fayad, Mohamed I et al. (2008) In vivo generation of dental pulp-like tissue by using dental pulp stem cells, a collagen scaffold, and dentin matrix protein 1 after subcutaneous transplantation in mice. J Endod 34:421-6
Balducci, Laura; Ramachandran, Amsaveni; Hao, Jianjun et al. (2007) Biological markers for evaluation of root resorption. Arch Oral Biol 52:203-8
George, A; Ramachandran, A; Albazzaz, M et al. (2007) DMP1--a key regulator in mineralized matrix formation. J Musculoskelet Neuronal Interact 7:308

Showing the most recent 10 out of 31 publications