Type I diabetics are at risk for bone loss and, with an increasing lifespan, are susceptible to osteoporosis and fractures. This is consistent with clinical and histological studies, suggesting that osteoblast differentiation is suppressed in diabetes. Osmoadaptation in eukaryotic cells involves the upregulation of PKC, p38 and AP-1 activities to induce expression of genes involved in cell volume regulation. If elevated, these signaling pathways can also have phenotypic consequences to developing and mature osteoblasts. We and others have demonstrated that AP-I family members influence osteoblast differentiation and gene expression. Correspondingly, long-term exposure of osteoblasts or calvaria to hyperosmotic conditions causes decreased mineralization. To test our hypothesis, the following Aims will be addressed: (1) determine levels of AP-1 and CRE activity and their importance in osteoblast responsiveness to hyperglycemia (HG) & hyperosmolarity (HO); (2) identify and test the roles of selected protein kinases in AP-1 and CRE activation by HG and HO; and (3) determine and test the roles of AP-1 and CRE activation in HG and HO modulation of target genes and bone phenotype in vivo. The first two Aims of this proposal will focus on examining molecular targets and signaling pathways modulated in response to hyperglycemia and hyperosmolarity. We hypothesize that the response to both conditions is mechanistically linked and will test if genes associated with an osmoadaptation are induced under HG conditions.
Aim 3 will test if our cellular and molecular models are consistent with in vivo responses to HG. In each Aim, we will test if we can block osteoblast osmoadaptation and restore osteoblast phenotype. Taken together, the goals of this study are to determine the effects of osmoadaptation on osteoblast phenotype and to identify those components of this mechanism that impede osteoblast differentiation, both in vitro and in vivo. Our results will suggest targets for ameliorating the effects of type I diabetes on bone. ? ?
|Motyl, Katherine J; McCauley, Laurie K; McCabe, Laura R (2012) Amelioration of type I diabetes-induced osteoporosis by parathyroid hormone is associated with improved osteoblast survival. J Cell Physiol 227:1326-34|
|McCabe, Laura; Zhang, Jing; Raehtz, Sandi (2011) Understanding the skeletal pathology of type 1 and 2 diabetes mellitus. Crit Rev Eukaryot Gene Expr 21:187-206|
|Coe, Lindsay M; Lippner, Dennean; Perez, Gloria I et al. (2011) Caspase-2 deficiency protects mice from diabetes-induced marrow adiposity. J Cell Biochem 112:2403-11|
|Coe, Lindsay M; Denison, Jeffery D; McCabe, Laura R (2011) Low dose aspirin therapy decreases blood glucose levels but does not prevent type i diabetes-induced bone loss. Cell Physiol Biochem 28:923-32|
|Coe, Lindsay M; Irwin, Regina; Lippner, Dennean et al. (2011) The bone marrow microenvironment contributes to type I diabetes induced osteoblast death. J Cell Physiol 226:477-83|
|Motyl, Katherine J; Raetz, Michelle; Tekalur, Srinivasan Arjun et al. (2011) CCAAT/enhancer binding protein ýý-deficiency enhances type 1 diabetic bone phenotype by increasing marrow adiposity and bone resorption. Am J Physiol Regul Integr Comp Physiol 300:R1250-60|
|Motyl, Katherine J; McCabe, Laura R; Schwartz, Ann V (2010) Bone and glucose metabolism: a two-way street. Arch Biochem Biophys 503:2-10|
|Motyl, Katherine J; McCabe, Laura R (2009) Leptin treatment prevents type I diabetic marrow adiposity but not bone loss in mice. J Cell Physiol 218:376-84|
|Motyl, Katherine J; Botolin, Sergiu; Irwin, Regina et al. (2009) Bone inflammation and altered gene expression with type I diabetes early onset. J Cell Physiol 218:575-83|
|McCabe, Laura R (2007) Understanding the pathology and mechanisms of type I diabetic bone loss. J Cell Biochem 102:1343-57|
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