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Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass

Abstract

Aging reduces the number of mesenchymal stem cells (MSCs) that can differentiate into osteoblasts in the bone marrow, which leads to impairment of osteogenesis. However, if MSCs could be directed toward osteogenic differentiation, they could be a viable therapeutic option for bone regeneration. We have developed a method to direct MSCs to the bone surface by attaching a synthetic high-affinity and specific peptidomimetic ligand (LLP2A) against integrin α4β1 on the MSC surface to a bisphosphonate (alendronate, Ale) that has a high affinity for bone. LLP2A-Ale induced MSC migration and osteogenic differentiation in vitro. A single intravenous injection of LLP2A-Ale increased trabecular bone formation and bone mass in both xenotransplantation studies and in immunocompetent mice. Additionally, LLP2A-Ale prevented trabecular bone loss after peak bone acquisition was achieved or as a result of estrogen deficiency. These results provide proof of principle that LLP2A-Ale can direct MSCs to the bone to form new bone and increase bone strength.

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Figure 1: LLP2A-Ale increases MSC migration and bone marrow stromal cell (BMSC) osteoblastic differentiation.
Figure 2: Treatment with LLP2A-Ale increases the homing and retention of the transplanted MSCs to bone.
Figure 3: Treatment with LLP2A-Ale increases trabecular bone mass in immunocompetent mice.
Figure 4: Treatment with LLP2A-Ale prevents age-related trabecular bone loss.
Figure 5: Treatment with LLP2A-Ale partially prevents trabecular bone loss and increases endosteal bone formation in OVX mice.

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Acknowledgements

The mouse MSCs used in this work were provided by the Texas A&M Health Science Center College of Medicine Institute for Regenerative Medicine at Scott & White through a grant from National Center for Research Resources of the US National Institutes of Health grant P40RR017447. This work was funded by the US National Institutes of Health grants NIAMS- 5R21AR057515 (to W.Y.), NIAM- R01AR043052 (to N.E.L.) and 1K12HD05195801 and was co-funded by the US National Institute of Child Health and Human Development (NICHD), the Office of Research on Women's Health (ORWH), the Office of Dietary Supplements (ODS) and the US National Institute of Aging (NIA).

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W.Y., N.E.L. and K.S.L. designed the study. M.G. and W.Y. performed the animal study, collected data from the cell cultures, biochemistry, microCT and bone histomorphometry and analyzed all the data. R.L. and L.M. designed and synthesized the compound LLP2A-Ale. R.L. participated in the synthesis of LLP2A-Ale, and K.L. synthesized the LLP2A-Ale. J.N. and P.Z. performed human MSC cultures and designed the experiments using the NOD/SCID/MPSVII mice. J.J. and M.S. performed immunohistochemistry and helped with the animal studies. B. Panganiban and R.O.R. performed biomechanical testing and analyzed data. All authors edited the paper.

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Correspondence to Wei Yao.

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The authors declare no competing financial interests.

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Guan, M., Yao, W., Liu, R. et al. Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass. Nat Med 18, 456–462 (2012). https://doi.org/10.1038/nm.2665

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