Systemic Administration of Allogeneic Mesenchymal Stem Cells Does Not Halt Osteoporotic Bone Loss in Ovariectomized Rats

Shuo Huang,Shuo Huang,Shuo Huang,Shuo Huang,Weidong Gu,Sien Lin,Sien Lin,Sien Lin,Jinfang Zhang,Jinfang Zhang,Gang Li,Gang Li,Gang Li,Yamei Liu,Lin Chen,Lin Chen,Yuxin Sun,Yuxin Sun,Liangliang Xu,Liangliang Xu,Liangliang Xu,Stan Gronthos

doi:10.1371/journal.pone.0163131

Abstract

Mesenchymal stem cells (MSCs) have innate ability to self-renew and immunosuppressive functions, and differentiate into various cell types. They have become a promising cell source for treating many diseases, particular for bone regeneration. Osteoporosis is a common metabolic bone disorder with elevated systemic inflammation which in turn triggers enhanced bone loss. We hypothesize that systemic infusion of MSCs may suppress the elevated inflammation in the osteoporotic subjects and slow down bone loss. The current project was to address the following two questions: (1) Will a single dose systemic administration of allogenic MSCs have any effect on osteoporotic bone loss? (2) Will multiple administration of allogenic MSCs from single or multiple donors have similar effect on osteoporotic bone loss? 18 ovariectomized (OVX) rats were assigned into 3 groups: the PBS control group, MSCs group 1 (receiving 2x106 GFP-MSCs at Day 10, 46, 91 from the same donor following OVX) and MSCs group 2 (receiving 2x106 GFP-MSCs from three different donors at Day 10, 46, 91). Examinations included Micro-CT, serum analysis, mechanical testing, immunofluorescence staining and bone histomorphometry analysis. Results showed that BV/TV at Day 90, 135, BMD of TV and trabecular number at Day 135 in the PBS group were significantly higher than those in the MSCs group 2, whereas trabecular spacing at Day 90, 135 was significantly smaller than that in MSCs group 2. Mechanical testing data didn’t show significant difference among the three groups. In addition, the ELISA assay showed that level of Rantes in serum in MSCs group 2 was significantly higher than that of the PBS group, whereas IL-6 and IL-10 were significantly lower than those of the PBS group. Bone histomorphometry analysis showed that Oc.S/BS and Oc.N/BS in the PBS group were significant lower than those in MSCs group 2; Ob.S/BS and Ob.N/BS did not show significant difference among the three groups. The current study demonstrated that systemic administration of allogenic MSCs had no obvious effect on osteoporotic bone loss in OVX rats when using the cells from the same donor; and repeated injection of allogeneic MSCs from different donors might promote bone loss in OVX rats. These findings indicate that despite allogenic MSCs systemic infusion is safe, their administration alone may not be an effective mean for preventing osteoporotic bone loss.

Highlights

Osteoporosis, a progressive systemic skeletal disease, is defined as a bone mineral density of 2.5 standard deviations or more below the average of young and healthy adults as measured by dual-energy X-ray absorptiometry [1]
The current study demonstrated that systemic administration of allogenic Mesenchymal stem cells (MSCs) had no obvious effect on osteoporotic bone loss in OVX rats when using the cells from the same donor; and repeated injection of allogeneic MSCs from different donors might promote bone loss in OVX rats
The quantitative analysis revealed that Bone volume (BV)/tissue volume (TV), bone mineral density (BMD) of TV and trabecular number in the phosphate buffered saline (PBS) group were significant higher than those in MSCs group 2 (Fig 3a–3c); Trabecular spacing in MSCs 2 group were significant larger than that in the PBS control group (Fig 3d); but there was no significant difference between MSCs group 1 and the PBS control group, as well as the MSCs group 1 and MSCs group 2

Summary

Introduction

Osteoporosis, a progressive systemic skeletal disease, is defined as a bone mineral density of 2.5 standard deviations or more below the average of young and healthy adults as measured by dual-energy X-ray absorptiometry [1]. Osteoporosis is characterized by a decrease in bone mass, bone mineral density (BMD) and microarchitecture deterioration of bone tissue, with a consequent increased risk of the fragility fracture which may lead to becoming bedridden with secondary complications or even a life threatening in the elderly [1, 2]. Osteoporosis commonly results from estrogen deficiency, characterized with inadequate bone formation, excessive bone resorption and failure to produce optimal bone mass and strength [3]. (2) Vitamin D and calcium supplementation, which is recommended as a baseline treatment in every patient with osteoporosis [3]; (3) Anti-resorptive drugs and bisphosphonates, which are most widely used due to high affinity for bone, long-term safety, inexpensive and effective for a broad spectrum of osteoporosis types [4]; (4) Anabolic drugs, which stimulate bone formation rather than preventing its loss.

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