A strategy for identifying osteoporosis risk genes.

The genetic factors that contribute to the susceptibility of osteoporosis are likely to be extremely heterogeneous, reflecting the complex genetic program that controls the cellular aspects of bone formation and remodeling. Because it is unlikely that current genetic methods will have the power to resolve multiple subtle genetic effects from the environmental contribution, biologic approaches will have to be developed to identify mechanistically similar forms of osteoporosis prior to applying more sophisticated molecular studies. This perspective article proposes a strategy that focuses on those subjects with an inherent impairment of bone formation as the primary cause of diminished bone mass. It views the impairment as a defect within the osteoprogenitor lineage and identifies the stage within the lineage where the progression digresses from normal. It is at the stage of diversion in the lineage that affected cells are isolated for extensive microarray studies with the intent to identify molecular pathways that are underperforming. The technological steps that have to be accomplished for this strategy to be successful rely heavily on promoter green fluorescent protein transgenes that can assess the extent and tempo of lineage progression in primary cells and intact bone, and that can allow for a relatively small subpopulation of cells from a primary bone cell culture to be isolated for molecular analysis. Initially, the strategy has to be validated in murine models with single gene defects affecting the performance of the osteoprogenitor lineage. The experience gained from murine models will allow a similar approach to be applied to humans.