MINERALIZATION OF PRIMARY BONE

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Primary or woven bone is distinguished in several respects. Morphologically primary bone is characterized by the speed of its deposition and mineralization, as well as the "disorganization" of its collagenous matrix. This "disorganization" has discouraged detailed structural analyses. Primary bone temporally replaces soft precursor tissue and is the first "mineralized bone" to occupy sites in long bone collars and craniofacial bones of the embryo, in healing fractures, and in adaptive skeletal gain in response to increased biomechanical stress. At many sites in the body, primary bone is subsequently replaced by lamellar bone. Although the mechanism for mineralization of lamellar bone is still controversial, a number of observations strongly suggest that the mechanism regulating primary bone formation and mineralization is distinct. Specifically, we have discovered an extracellular biomarker, BAG-75, that is exclusively deposited at focal sites (BMP) destined to become mineralized primary bone. Our results demonstrate that this occurs both in vivo and in vitro in several well accepted differentiating osteogenic cell culture models, as well as in the UMR106-01 BSP cell line. The latter is distinguished by the speed of this process and the large number of mineralizing foci which form. While prior published reports may have identified BMP morphologically as crystal ghosts and nodules, lack of a biomarker has slowed characterization of these sites. We hypothesize that BMP contain components essential for the initial nucleation and rapid completion of the mineralization process in embryonic and healing bone. Our proposal will test this hypothesis by examining four specific aims. Our experimental strategy will utilize cell culture models to carry out proteomic and functional studies on isolated BMP. Key findings will be validated with primary bone produced in the rodent marrow ablation model. Results of this work should better define the differences between primariy and lamellar bone, as well as aid in the diagnosis and treatment of osteoporosis and atherosclerosis.