Bone remodeling involves the synchronized activity of osteoblasts and osteoclasts and results in a cyclical succession of bone resorptive and formative phases. This orderly cellular activity requires efficient mechanisms of cell-cell interactions within the bone microenvironment. During the previous funding cycle, we have found that osteob1asts express members of the cadherin superfamily of cell adhesion molecules, in particular cadherin-11 (cadl1) and N-cadherin (Ncad). These two cadherins are an integral part of the phenotypic fingerprinting that defines cells of the osteogenic lineage as they differentiate into fully mature osteoblasts. We also found that disruption of cadherin mediated cell-cell adhesion by either inhibitory peptides or by expression of a dominant-negative cadherin mutant severely compromises the ability of osteoblastic cells to produce matrix proteins and mineralize in vitro. In the next funding period, we propose to extend these observations to in vivo models, and test the central hypothesis that cell-cell interactions mediated by cadherins are required for osteoblast function and bone remodeling in vivo. The proposed experimentation will make use of genetically engineered mice models with modified cadherin expression or function, some of them developed in our laboratory. These models will be used in the following three specific aims that are designed to address three specific questions: 1: Does interference with osteoblast cadherin expression or function lead to reduced bone formation and development of abnormal bone mass development and blunted response to osteoblast stimulation in vivo? 2: Is osteoblast maturation and function compromised by disruption of Ncad and/or cad11 genes? 3: Can other cadherins compensate for lack of Ncad or cad11 in osteoblasts? We anticipate that Ncad and cadl1 serve critical, common functions and thus interference with either Ncad and cad11 expression or function will result in abnormal bone formation, osteoblast activity, and response to intermittent PTH. These studies will disclose a novel mechanism by which the activity of bone forming cells is controlled invivo Alterations of cadherin mediated cell-cell interactions by hormonal imbalances or aging may lead to osteoblast failure.
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