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The Role of Heparan Sulfate and Perlecan in Bone-regenerative Procedures

¹ Agenta Biotechnologies, Inc., OADI Technology Center, 2800 Milan Court, Suite 382, Birmingham, AL 35211, USA; and
² Biomaterials & Tissue Engineering, Graduate School of Biomedical Engineering, University of New South Wales, Australia

View larger version (21K): [in a new window]   Figure 1. Cartoon of perlecan domain structure with 3 glycosaminoglycan chains, typically heparan sulfate, covalently attached to domain I of the protein core. Various homologies and purported functions are ascribed to each domain. SMC, smooth-muscle cell; EC, endothelial cell; FGF, fibroblast growth factor; MMP, matrix metalloproteinase; EGF, epithelial growth factor; LDL, low-density lipoprotein; ECM, extracellular matrix.

View larger version (28K): [in a new window]   Figure 2. Proposed modulation of healing by heparan-sulfate-decorated perlecan via transfection of core domain 1 sequence. (A) Transfection of domain I of perlecan into cells via viral vector. (1) Transfection of domain I of perlecan into cells via non-replicative viral vector. (2) Transcription and translation of recombinant DNA by host. (3) The truncated recombinant domain I protein core is trafficked to the Golgi for glycosylation. (4) Release of perlecan domain I decorated with heparan sulfate (HS) that has been specifically engineered by the cells in response to their status and environment. (5) The truncated and decorated recombinant perlecan is incorporated into the surrounding pericellular environment. (B) Growth factor binding and release by heparan-sulfate-decorated perlecan domain I. (6) FGF (green circles) binds to extracellular HS-decorated domain I of recombinant perlecan expressed by the cells in the vicinity. (7) Degradation of protein core of domain I by proteases produced at sites of wound healing, which releases HS/FGF fragments. (8) Free HS/FGF fragments. (C) Activation of growth factor receptors and downstream healing pathways. (9) Binding of FGF+/– HS activates receptor kinases that phosphorylate sites in the receptor. (10) Activation of intracellular signaling pathways leading to the activation of various phosphokinase enzymes (e.g., MAP kinase pathway) that leads to the activation of transcription factors. (11) Modulation of transcription relative to migration, proliferation, and differentiation to improve wound healing.