Nanoparticulate Mineralized Collagen Glycosaminoglycan Decreases Osteoclast Activity via Upregulation of Osteoprotegerin
David S. Foulad, MD1, Xiaoyan Ren, PhD1, Timothy A. Miller, MD1, Brendan A. Harley, SM, ScD2, Justine C. Lee, MD, PhD1.
1Division of Plastic and Reconstructive Surgery, University of California, Los Angeles, David Geffen School of Medicine, and Greater Los Angeles VA Healthcare System, Los Angeles, CA, USA, 2Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Roger Adams Lab, Urbana, IL, USA.
PURPOSE: The increasing understanding that the extracellular matrix (ECM) can serve instructive roles in differentiation has resulted in significant interest in the synthesis of ECM-inspired regenerative materials. We recently described a nanoparticulate mineralized collagen-glycosaminoglycan (MC-GAG) material that regenerates calvarial defects without preloading with progenitor cells and without addition of exogenous growth factors. To understand the interactions between MC-GAG and the microenvironment, this work evaluates the effects of MC-GAG-mediated osteogenesis on osteoclast activity.
METHODS: Primary human mesenchymal stem cells (hMSCs) seeded on non-mineralized collagen-glycosaminoglycan (Col-GAG) or MC-GAG were cultured with and without primary human osteoclasts (hOCs). hMSC osteogenic differentiation was assessed using micro-computed tomography and western blot (WB) analysis. Osteoclast resorptive activity was assessed using pit assays. Levels of osteoprotegerin (OPG), a RANKL decoy receptor, were determined with WB and ELISA.
RESULTS: hOCs increased osteogenic differentiation of hMSCs in co-cultures on either material, albeit significantly higher in MC-GAG. Unlike co-cultures with Col-GAG, hMSCs cultured on MC-GAG decreased osteoclast-mediated resorption. MC-GAG scaffolds induced earlier and more robust upregulation of OPG protein expression and secretion in hMSCs.
CONCLUSION: The mechanistic interactions between ECM-based materials and biology have become increasingly important to regeneration. This current work demonstrates capabilities of MC-GAG to both increase osteogenesis and decrease osteoclast resorption via OPG, thus suggesting that the in vivo efficacy for calvarial regeneration by MC-GAG may be related to regulation of both processes.
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