Bone marrow-derived heparan sulfate potentiates the osteogenic activity of bone morphogenetic protein-2 (BMP-2).
Lowering the efficacious dose of bone morphogenetic protein-2 (BMP-2) for the repair of critical-sized bone defects is highly desirable, as supra-physiological amounts of BMP-2 have an increased risk of side effects and a greater economic burden for the healthcare system. To address this need, we explored the use of heparan sulfate (HS), a structural analog of heparin, to enhance BMP-2 activity. We demonstrate that HS isolated from a bone marrow stromal cell line (HS-5) and heparin each enhances BMP-2-induced osteogenesis in C2C12 myoblasts through increased ALP activity and osteocalcin mRNA expression. Commercially available HS variants from porcine kidney and bovine lung do not generate effects as great as HS5. Heparin and HS5 influence BMP-2 activity by (i) prolonging BMP-2 half-life, (ii) reducing interactions between BMP-2 with its antagonist noggin, and (iii) modulating BMP2 distribution on the cell surface. Importantly, long-term supplementation of HS5 but not heparin greatly enhances BMP-2-induced bone formation in vitro and in vivo. These results show that bone marrow-derived HS effectively supports bone formation, and suggest its applicability in bone repair by selectively facilitating the delivery and bioavailability of BMP-2.
Stem Cells and Tissue Repair Group, Institute of Medical Biology, A*STAR, Biopolis, Singapore 138648, Singapore.
Diah S
DS
Bramono
Sadasivam
S
Murali
Bina
B
Rai
Ling
L
Ling
Wei Theng
WT
Poh
Zophia Xuehui
ZX
Lim
Gary S
GS
Stein
Victor
V
Nurcombe
Andre J
AJ
van Wijnen
Simon M
SM
Cool
D000818:Animals; D001682:Biological Availability; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002828:Choristoma / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D002852:Chromatography, Ion Exchange; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004187:Disaccharides / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D006493:Heparin / Q000494:pharmacology; D006497:Heparan Sulfate / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D034421:Sus scrofa; D000099176:Noggin Protein
D055396:Bone Morphogenetic Protein 2; D052005:Bone Morphogenetic Protein Receptors, Type I; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D004187:Disaccharides; D006493:Heparin; D006497:Heparan Sulfate; D000099176:Noggin Protein