title: Affinity-selected heparan sulfate for bone repair.
abstract: Bone morphogenetic protein (BMP)-2 is a potent bone healing compound produced at sites of bone trauma. Here we present a therapeutic strategy to harness the activity of endogenously produced BMP-2 by delivery of an affinity-matched heparan sulfate (HS) glycos aminoglycan biomaterial that increases the bioavailability, bioactivity and half-life of this growth factor. We have developed a robust, cost effective, peptide-based affinity platform to isolate a unique BMP-2 binding HS variant from commercially available preparations of HS, so removing the manufacturing bottleneck for their translation into the clinic. This affinity-matched HS enhanced BMP-2-induced osteogenesis through improved BMP-2 kinetics and receptor modulation, prolonged pSMAD signaling and reduced interactions with its antagonist noggin. When co-delivered with a collagen implant, the HS was as potent as exogenous BMP-2 for the healing of critical-sized bone defects in rabbits. This affinity platform can be readily tuned to isolate HS variants targeted ata range of clinically-relevant growth and adhesive factors.
authors: Glycotherapeutics Group, Institute of Medical Biology, A*STAR, 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore.
authors: S
authors: S
authors: Murali
authors: B
authors: B
authors: Rai
authors: C
authors: C
authors: Dombrowski
authors: J L J
authors: JL
authors: Lee
authors: Z X H
authors: ZX
authors: Lim
authors: D S
authors: DS
authors: Bramono
authors: L
authors: L
authors: Ling
authors: T
authors: T
authors: Bell
authors: S
authors: S
authors: Hinkley
authors: S S
authors: SS
authors: Nathan
authors: J H
authors: JH
authors: Hui
authors: H K
authors: HK
authors: Wong
authors: V
authors: V
authors: Nurcombe
authors: S M
authors: SM
authors: Cool
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001857:Bone Matrix / Q000187:drug effects / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000737:chemistry / Q000378:metabolism; D001861:Bone Regeneration / Q000187:drug effects; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology*; D002113:Calcification, Physiologic / Q000187:drug effects; D002352:Carrier Proteins / Q000494:pharmacology; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D004187:Disaccharides / Q000032:analysis; D006497:Heparan Sulfate / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D010012:Osteogenesis / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D011817:Rabbits; D014158:Transcription, Genetic / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects*; D055114:X-Ray Microtomography; D000099176:Noggin Protein
chemical_list: D000469:Alkaline Phosphatase; D000925:Anticoagulants; D055396:Bone Morphogenetic Protein 2; D002352:Carrier Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D004187:Disaccharides; D006497:Heparan Sulfate; D000099176:Noggin Protein