Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass.
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.
Musculoskeletal Research Group, Department of Internal Medicine, University of California at Davis Medical Center, Sacramento, California, USA.
Min
M
Guan
Wei
W
Yao
Ruiwu
R
Liu
Kit S
KS
Lam
Jan
J
Nolta
Junjing
J
Jia
Brian
B
Panganiban
Liping
L
Meng
Ping
P
Zhou
Mohammad
M
Shahnazari
Robert O
RO
Ritchie
Nancy E
NE
Lane
D019386:Alendronate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001861:Bone Regeneration / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D054443:Cell Migration Assays; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007121:Immunocompetence / Q000235:genetics; D039041:Integrin alpha4beta1 / Q000737:chemistry / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D010012:Osteogenesis / Q000187:drug effects*; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D004151:Dipeptides; D039041:Integrin alpha4beta1; C512274:LLP2A compound; D057786:Peptidomimetics; D010671:Phenylurea Compounds; D019386:Alendronate