BAG-75: UNIQUE MARKER OF PRIMARY BONE FORMATION

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DESCRIPTION (provided by applicant): Primary bone is defined morphologically as bone formed directly from soft mesenchymal tissue without a calcified cartilage or mineralized precursor stage. Long bones develop postnatally by the apposition of primary bone upon cartilaginous remnants in the primary spongiosa, while all or parts of the frontal, parietal, occipital, temporal, maxilla, and mandible bones of the craniofacial system form and remain as primary bone. Research on primary bone has received less emphasis in the past and the true extent of cellular and biochemical differences between primary and lamellar bone are unknown. While lamellar bone represents the mature structure, primary bone is the precursor of lamellar bone-capable of being formed de novo. Primary bone can be distinguished from lamellar (cortical) bone on the basis of the faster speed of its deposition, exquisite spatial patterning and mineralization, its apparent specific enrichment in acidic phosphoprotein BAG-75, and its increased sensitivity to applied biomechanical forces and systemic hormones. We propose that BAG-75, through its strong propensity to self-associate into supramolecular microfibrillar complexes, serves as a structural framework defining the volume of primary bone matrix to be subsequently calcified. The goal of this proposal is to address the hypothesis that BAG-75 (bone acidic glycoprotein-75) is a unique gene product whose expression is restricted to active de novo calcification reactions, and, which contains more than 40 casein kinase phosphorylation sites, one or more polyglutamic acid calcium-binding motifs, N- and O-linked oligosaccharide attachment sites, and a repetitive modular primary structure facilitating home-and heteropolymeric associations required for formation and mineralization of primary bone. This project fits two main objectives of the R2 1 mechanism: to support innovative and high-risk research relevant to the primary research mission areas of NIDCR, and, initial development of a line of research upon which significant future studies can be based. For example, if a BAG-75 framework serves a key organizational role, a surface coating of BAG-75 could improve the stability of dental and orthopedic implants; 8-9 percent of the 1 37,000 hip implants in the U.S. each year require revision surgery within 5-10 years. We envision that a BAG-75 coated, non-cemented implant would self-associate with host-derived BAG-75 to form a seamless natural framework leading to deposition of other matrix components and mineralization within submicron distances of the implant surface--improving functional longevity of implants. Since primary bone is capable of being formed de novo, future determination of the BAG-75 promoter structure could form the basis of a new gene therapy approach to reverse losses in trabecular bone connectivity and alveolar bone volume with aging by targeting local stimulatory agents to primary bone osteoprogenitor cells expressing BAG-75, thus enhancing bone volume and restoring lost trabecular connectivity. Stimulation of appositional formation by lamellar bone would not be expected to have the same effect. These future functional studies require determination of the BAG-75 cDNA sequence.