DDR2, a Novel Collagen Receptor, and Mineralization

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DESCRIPTION (provided by applicant): Fibrillar type I collagen is the major framework in most mineralized tissues in vertebrates. Its structural role in mineralization is well recognized but its potential role as a ligand to control matrix organization/mineralization is essentially unknown. Discoidin domain receptor 2 (DDR2) is a newly identified fibrillar collagen receptor found in several tissues and organs, however, its presence and roles in mineralized tissues are unknown. Our preliminary studies indicate that DDR2 is highly expressed by osteoblastic cells and that its inhibition leads to severely affected collagen matrix organization/mineralization and altered expression of type I collagen and related MMPs (i.e. rodent interstitial collagenase and gelatinase). Our hypothesis is that signaling through DDR2 in osteoblastic cells modulates collagen matrix organization and mineralization by regulating the level of collagen synthesis and degradation. To test this hypothesis, we propose: 1. To investigate the effects of lowered DDR2 expression in MC3T3-E1 cells on matrix organization and mineralization.1 a. To establish single-cell derived clones expressing lower levels of DDR2. 1b. To evaluate the mRNA expression levels of COLI and interstitial collagen-associated MMPs (MMP2, 13).1c. To characterize the content, maturation, organization and mineralization pattern of collagen matrix produced by these clones; 2. To investigate the effects of overexpression of DDR2 in MC3T3-E1 cells on matrix organization and mineralization. 2a. To establish single-cell derived clones expressing higher levels of DDR2. 2b. To evaluate the mRNA expression levels of COLI and interstitial collagen-associated MMPs (MMP2, 13). 2c. To characterize the content, maturation, organization and mineralization pattern of collagen matrix produced by these clones; 3. To investigate the activation of COLI (alpha1) and MMP2 promoters through DDR2 signaling. The results of this research would provide insights into novel regulatory roles of this newly identified collagen receptor, DDR2, in bone physiology.