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

Abstract

Aging reduces the number of mesenchymal stem cells (MSCs) 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 the 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 high affinity for bone. LLP2A-Ale increased MSCs migration and osteogenic differentiation in vitro. A single intravenous injection of LLP2A-Ale increased trabecular bone formation and bone mass in both xenotransplantation and immune competent mice. Additionally, LLP2A-Ale prevented trabecular bone loss after peak bone acquisition was achieved or following estrogen deficiency. These results provide a proof of principle that LLP2A-Ale can direct MSCs to the bone to form new bone and increase bone strength.

Allogeneic and Xenogeneic Transplantation of Adipose-Derived Stem Cells in Immunocompetent Recipients Without Immunosuppressants

“…First, murine BMSCs, unlike their human equivalent, lack major histocompatibility complex (MHC) class II expression [13], and second, T-cell inhibition by BMSCs requires cell contact in mice but is mediated by soluble factors in humans [14,15]. In any event, reports of successful xenotransplantation with BMSCs from various species continue to appear frequently; for example, rat BMSC for bone formation in rabbit [16], human BMSC for spinal cord injury in rat [17,18], and human BMSC for bone formation in mice [19].…”

Mesenchymal stem cells in tumor development

“…These activities include the regulation of vital processes, such as hematopoiesis, 49,66,67 the preservation of blood vessel integrity 68 or bone maintenance. 69 More appreciated, however, are the functions of MSCs in cases of wound healing and tissue repair. 70 In these respects, current models suggest that MSCs are dispatched from their niches in response to systemic signals derived from injured tissues (e.g., ref.…”

β-Ecdysone Augments Peak Bone Mass in Mice of Both Sexes

“…For the right midfemur, the scanning was performed at the middle femur continuing proximally 1 mm. All the slices were used to evaluate cortical bone volume and cortical bone thickness [19,45,46].…”

“…The middle right femurs were embedded in methyl methacrylate and sectioned to 30 lm using a Leica SP1600 microtome (Leica Microsystems Inc). Bone histomorphometry was performed using the Bioquant imaging analysis system (Bioquant Image Analysis Corporation, Nashville, TN, USA) [19,45,46]. Lumbar vertebral samples from all groups and only FX from the intact groups were evaluated for bone histomorphometry.…”

“…Values for the maximum load were determined. A measure of work to failure was estimated by calculating the area under the load versus displacement curve [19,37,44,45].…”