Age-related bone loss occur because of an inadequate supply of osteoblasts at the bone remodeling site, compared to the demand for them created by osteoclastic bone resorption. Furthermore, decreased osteoblastogenesis in old age is accompanied by an increase in adipogenesis in the bone marrow. Based on evidence that osteoblasts and adipocytes are closely related and originate from a common mesenchymal progenitor, the following working hypothesis is proposed: the osteopenia associated with aging is the result of changes in mesenchymal cell differentiation in the bone marrow, such that adipogenesis increases at the expense of osteoblastogenesis. The molecular bases of these changes are over- or under-expression of genes responsible for the decision of the common progenitors to commit to the particular differentiation pathway. The bipotential cell line, UAMS-33, will be used as a model to identify molecular components which determine the lineage commitment of mesenchymal progenitors of the bone marrow. This cell line is derived from adult murine bone marrow and is able to differentiate into adipocytes or osteoblasts after appropriate stimulation. These cells also exhibit the unique property that when stimulated simultaneously with both adipocytic and osteoblastic stimuli, the phenotype expressed depends on their state of growth at the time of stimulation. This feature will be used to detect and identify positive and negative regulators of commitment to the adipocytic or osteoblastic lineage using subtracted cDNA libraries. For further analysis, a gene that is expressed exclusively and early during differentiation will be selected with priority placed on those genes exhibiting homology to known transcription factors, signaling molecules, and growth factors. The role of this gene in determining commitment to a particular differentiation pathway will be examined by abrogating its expression with antisense RNA placed under the control of inducible promoter. The results of these studies will set the stage for further study on the role of regulators of commitment to specific marrow stoma cell lineages in murein models of aging.
| Lecka-Czernik, Beata; Moerman, Elena J; Grant, David F et al. (2002) Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiation. Endocrinology 143:2376-84 |
| Lecka-Czernik, B; Gubrij, I; Moerman, E J et al. (1999) Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPARgamma2. J Cell Biochem 74:357-71 |
