Article

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

Musculoskeletal Research Group, Department of Internal Medicine, University of California at Davis Medical Center, Sacramento, California, USA.
Nature medicine (Impact Factor: 28.05). 02/2012; 18(3):456-62. DOI: 10.1038/nm.2665
Source: PubMed

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.

3 Followers
 · 
164 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Beta-ecdysone (βEcd) is a phytoecdysteroid found in the dry roots and seeds of the asteraceae and achyranthes plants, and is reported to increase osteogenesis in vitro. Since glucocorticoid (GCs) excess is associated with a decrease in bone formation, the purpose of this study was to determine if treatment with βEcd could prevent GC-induced osteoporosis. Two-month-old male Swiss-Webster mice (n=8-10/group) were randomized to either placebo or slow release prednisolone pellets (3.3mg/kg/d) and treated with vehicle control or βEcd (0.5mg/kg/d) for 21days. GC treatment inhibited age-dependent trabecular gain and cortical bone expansion and this was accompanied by a 30-50% lower bone formation rate (BFR) at both the endosteal and periosteal surfaces. Mice treated with only βEcd significantly increased bone formation on endosteal and periosteal bone surfaces, and increased cortical bone mass were their controls to compare to GC alone. Concurrent treatment of βEcd and GC completely prevented the GC-induced reduction in BFR, trabecular bone volume and partially prevented cortical bone loss. In vitro studies determined that βEcd prevented the GC increase in autophagy of the bone marrow stromal cells as well as in whole bone. In summary, βEcd prevented GC induced changes in bone formation, bone cell viability and bone mass. Additional studies are warranted of βEcd for the treatment of GC induced bone loss. Copyright © 2015 Elsevier Inc. All rights reserved.
    Bone 01/2015; 74. DOI:10.1016/j.bone.2015.01.001 · 4.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: One of the strongest predictors for osteoporosis is peak bone mass. Interventions to augment peak bone mass have yet to be developed. β-Ecdysone (βEcd), a natural steroid-like compound produced by arthropods to initiate metamorphosis, is believed to have androgenic effects and so may be used to augment bone mass. The purpose of this study was to use both male and female (1) gonadal-sufficient; and (2) -insufficient mice to investigate sex differences in terms of bone development and structure after βEcd administration. Two-month-old male and female Swiss-Webster mice were randomized to receive either vehicle or βEcd (0.5 mg/kg) for 3 weeks. In a separate experiment to evaluate the effects of βEcd on sex hormone-deficient mice, gonadectomy was performed in male (orchiectomy [ORX]) and female mice (ovariectomy [OVX]). Sham-operated and the ORX/OVX mice were then treated for 3 weeks with βEcd. Primary endpoints for the study were trabecular bone structure and bone strength. In male mice, the trabecular bone volume was 0.18 ± 0.02 in the placebo-treated (PL) and 0.23 ± 0.02 in the βEcd-treated group (p < 0.05 versus PL); and 0.09 ± 0.01 in the ORX group (p < 0.05 versus PL) and 0.12 ± 0.01 in the ORX + βEcd group. Vertebral bone strength (maximum load) was 43 ± 2 in PL and 51 ± 1 in the βEcd-treated group (p < 0.05 versus PL); and 30 ± 4 in the ORX group (p < 0.05 versus PL) and 37 ± 3 in the ORX + βEcd group. In female mice, trabecular bone volume was 0.23 ± 0.02 in PL and 0.26 ± 0.02 in the βEcd-treated group (p < 0.05 versus PL); and 0.15 ± 0.01 in the OVX group (p < 0.05 versus PL) and 0.14 ± 0.01 in the OVX + βEcd group. Maximum load of the vertebrae was 45 ± 2 in PL and 48 ± 4 in the βEcd-treated group; and 39 ± 4 in the OVX group (p < 0.05 versus PL) and 44 ± 4 in the OVX + βEcd group. These findings suggest the potential use of βEcd in the augmentation of bone mass in growing male and female mice. It may also partially prevent the detrimental effects of gonadectomy on trabecular bone. Our results support the potential use of βEcd or nature products that are rich in βEcd to augment peak bone mass. βEcd may differ from the other anabolic hormone treatments that may have severe side effects such as serious cardiac complications. However, its effects on humans remain to be determined.
    Clinical Orthopaedics and Related Research 03/2015; DOI:10.1007/s11999-015-4246-5 · 2.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Several metabolic, genetic and oncogenic bone diseases are characterized by defective or excessive bone formation. These abnormalities are caused by dysfunctions in the commitment, differentiation or survival of cells of the osteoblast lineage. During the recent years, significant advances have been made in our understanding of the cellular and molecular mechanisms underlying the osteoblast dysfunctions in osteoporosis, skeletal dysplasias and primary bone tumors. This led to suggest novel therapeutic approaches to correct these abnormalities such as the modulation of WNT signaling, the pharmacological modulation of proteasome-mediated protein degradation, the induction of osteoprogenitor cell differentiation, the repression of cancer cell proliferation and the manipulation of epigenetic mechanisms. This article reviews our current understanding of the major cellular and molecular mechanisms inducing osteoblastic cell abnormalities in age-related bone loss, genetic skeletal dysplasias and primary bone tumors, and discusses emerging therapeutic strategies to counteract the osteoblast abnormalities in these disorders of bone formation.
    Cellular and Molecular Life Sciences CMLS 12/2014; 72(7). DOI:10.1007/s00018-014-1801-2 · 5.86 Impact Factor

Full-text (2 Sources)

Download
13 Downloads
Available from
Mar 24, 2015