Induction of Senile Osteoporosis in Normal Mice by Intra-Bone Marrow-Bone Marrow Transplantation from Osteoporosis-Prone Mice

Abstract

A P6 substrain of the senescence accelerated mouse (SAMP6) spontaneously develops osteoporosis early in life. These mice show the clinical signs of osteoporosis, such as elevated levels of urinary deoxypyridinoline (Dpd), decreased bone mineral density (BMD), and a significant loss of trabecular and cortical bone thickness at 12 months of age. Here, we describe the transfer of osteoporosis to a normal strain by the injection of bone marrow cells from SAMP6 donors directly into the bone marrow cavity (intrabone marrow-bone marrow transplantation [IBM-BMT]).More than 1 month after IBM-BMT, hematolymphoid cells were completely reconstituted by donor-derived cells, and bone marrow stromal cells that could differentiate into osteocytes were also found to be of donor origin. In addition, the recipient C57BL/6 mouse showed the features of osteoporosis in the trabecular bone. Decreases in BMD and increases in urinary Dpd were also observed. When the message levels of cytokines (interleukin [IL]-11, IL-6, receptor activator of NF-B ligand [RANKL], osteoprotegerin, macrophage-colony-stimulating factor, and insulin-like growth factor-1) were examined by reverse transcriptionpolymerase chain reaction (RT-PCR) and real-time RT-PCR analysis, IL-6 and IL-11 were reduced to a level similar to that in SAMP6 mice, whereas that of RANKL was increased. These findings indicate that not only the hemopoietic system but also the bone marrow microenvironment are reconstituted as a result of IBM-BMT, and suggest that the development of senile osteoporosis might be attributable to "stem cell disorders." STEM CELLS 2007;25: 1356 -1363 Disclosure of potential conflicts of interest is found at the end of this article.

Classical Models of Senile Osteoporosis

“…23 Interestingly, bone marrow transplantation from normal to recipient SAMP6 mice resulted in a significant increase in trabecular bone and BMD. [24][25][26] This finding confirms that the defect in SAMP6 mice originates in bone marrow and can be rescued by normal marrow.…”

Zinc Finger Protein 467 Is a Novel Regulator of Osteoblast and Adipocyte Commitment

“…These cells were transduced with either vector control or sense Zfp467 containing constructs. Intra-tibial injection methods have been used successfully to study agerelated bone diseases including osteoporosis, and the ability of donor cells to proliferate and survive in recipient bone marrow following intra-tibial injections has been confirmed in previous studies (35,36). The presence of introduced calvarial cells was confirmed 7 days post-inoculation by Q-PCR for empty vector or transgenic Zfp467 transcripts (Fig.…”

Senescence‐associated intrinsic mechanisms of osteoblast dysfunctions

“…However, some studies have demonstrated age-related changes in the concentration of osteoblast-active molecules such as IGF-I and TGF-b in the bone matrix (Bismar et al, 1999;Seck et al, 1999). Also, an osteoporotic phenotype was created in a normal healthy mouse by intramedullary injection of bone marrow cells obtained from the senescence-accelerated mouse prone 6 (SAMP6), a well-characterized model for accelerated aging, including an osteoporotic phenotype (Ueda et al, 2007). Owing to the limited engraftment of the transplanted cells, one explanation of these data could be a defective microenvironment in SAMP6 senescent and osteoporotic cells.…”