Drug-induced gingival overgrowth is a common and undesirable side effect of long-term immunosuppressive therapy, but the molecular basis of this disorder remains poorly understood. Basic fibroblast growth factor (bFGF), also called fibroblast growth factor 2 (FGF-2), has been implicated in the development of overgrowth disease, including that of the gingiva. Following its biosynthesis, bFGF is sequestered by the extracellular matrix (ECM), and it is release of bFGF from the ECM which is likely to govern its bioavailability to local tissues. Sequestration of bFGF occurs via specific binding interactions with heparan sulfate (HS) glycosaminoglycans attached to core proteins embedded in the ECM. Our laboratories have identified a novel Heparan Sulfate Interacting Protein (HIP) which recognizes specific HS sequences and thereby modulates the interactions of bFGF with HS chains in the gingival ECM. We hypothesize that HIP plays a key regulatory role in modulating bFGF bioavailability during the development of gingival overgrowth in immunosuppressed patients receiving cyclosporine A (CsA). This proposal includes studies designed to evaluate two molecular models for the regulation of bFGF bioavailability by HIP. These two models include the possibilities that HIP may act as a heparinase inactivator in gingival tissues, or alternatively as a facilitator of bFGF release from the gingival ECM. These studies will be complemented by studies to evaluate the levels and distribution of HIP transcript and HIP protein in gingiva from normal individuals and in individuals with CsA-induced gingival overgrowth. Studies to assess the ability of HIP to modulate bFGF-stimulated growth of gingival fibroblasts in primary culture will also be performed. Together, these studies will provide a better understanding of the cellular and molecular events of gingival overgrowth, and provide the opportunity to develop novel non-surgical therapies for prevention or treatment of gingival overgrowth.
