Osteogenesis on nanoparticulate mineralized collagen scaffolds via autogenous activation of the canonical BMP receptor signaling pathway.
Skeletal regenerative medicine frequently incorporates deliverable growth factors to stimulate osteogenesis. However, the cost and side effects secondary to supraphysiologic dosages of growth factors warrant investigation of alternative methods of stimulating osteogenesis for clinical utilization. In this work, we describe growth factor independent osteogenic induction of human mesenchymal stem cells (hMSCs) on a novel nanoparticulate mineralized collagen glycosaminoglycan scaffold (MC-GAG). hMSCs demonstrated elevated osteogenic gene expression and mineralization on MC-GAG with minimal to no effect upon addition of BMP-2 when compared to non-mineralized scaffolds (Col-GAG). To investigate the intracellular pathways responsible for the increase in osteogenesis, we examined the canonical and non-canonical pathways downstream from BMP receptor activation. Constitutive Smad1/5 phosphorylation with nuclear translocation occurred on MC-GAG independent of BMP-2, whereas Smad1/5 phosphorylation depended on BMP-2 stimulation on Col-GAG. When non-canonical BMPR signaling molecules were examined, ERK1/2 phosphorylation was found to be decreased in MC-GAG but elevated in Col-GAG. No differences in Smad2/3 or p38 activation were detected. Collectively, these results demonstrated that MC-GAG scaffolds induce osteogenesis without exogenous BMP-2 addition via endogenous activation of the canonical BMP receptor signaling pathway.
Division of Plastic and Reconstructive Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA; Division of Plastic and Reconstructive Surgery, Greater Los Angeles VA Healthcare System, Los Angeles, CA 90073, USA.
Xiaoyan
X
Ren
Research Service, Greater Los Angeles VA Healthcare System, USA.
David
D
Bischoff
Department of Chemical and Biomolecular Engineering, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Daniel W
DW
Weisgerber
Department of Pathology, Greater Los Angeles VA Healthcare System, USA.
Michael S
MS
Lewis
Division of Plastic and Reconstructive Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA; Division of Plastic and Reconstructive Surgery, Greater Los Angeles VA Healthcare System, Los Angeles, CA 90073, USA.
Victor
V
Tu
Research Service, Greater Los Angeles VA Healthcare System, USA.
Dean T
DT
Yamaguchi
Division of Plastic and Reconstructive Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA; Division of Plastic and Reconstructive Surgery, Greater Los Angeles VA Healthcare System, Los Angeles, CA 90073, USA.
Timothy A
TA
Miller
Department of Chemical and Biomolecular Engineering, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Brendan A C
BA
Harley
Division of Plastic and Reconstructive Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA; Division of Plastic and Reconstructive Surgery, Greater Los Angeles VA Healthcare System, Los Angeles, CA 90073, USA. Electronic address: justine@ucla.edu.
Justine C
JC
Lee
D000469:Alkaline Phosphatase / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D024042:Collagen Type I / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D010012:Osteogenesis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism; D054457:Tissue Scaffolds / Q000737:chemistry*; D015854:Up-Regulation / Q000187:drug effects; D055114:X-Ray Microtomography
D024042:Collagen Type I; D006025:Glycosaminoglycans; D012333:RNA, Messenger; D051785:Smad Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D052004:Bone Morphogenetic Protein Receptors; D000469:Alkaline Phosphatase
BMP; Biomimetic material; Nanoparticulate mineralization; Osteogenesis