Prevention of Senile Osteoporosis in SAMP6 Mice by Intrabone Marrow Injection of Allogeneic Bone Marrow Cells

Abstract

The SAMP6 mouse (a substrain of senescenceaccelerated mice) spontaneously develops osteoporosis early in life and is, therefore, a useful model for examining the mechanisms underlying osteoporosis. We have recently established a new bone marrow transplantation (BMT) method: the bone marrow cells (BMCs) of normal allogeneic mice are directly injected into the bone marrow (BM) cavity of irradiated (5.5 Gy × 2) recipients (IBM-BMT). Using IBM-BMT, we attempted to prevent osteoporosis in SAMP6 mice. The hematolymphoid system was completely reconstituted with donor-type cells after IBM-BMT. Thus-treated SAMP6 mice showed marked increases in trabecular bones even at 12 months of age, and the bone mineral density remained similar to that of normal B6 mice. In concordance with these findings, urinary deoxypyridinoline also remained continuously low until 10 months of age, indicating that IBM-BMT was effective in the prevention of bone absorption.In addition to the above, BM stromal cells in the treated SAMP6 mice were replaced with donor stromal cells, and the message level of interleukin-11 (IL-11), which is produced by the BM stromal cells and is known as an important factor in the regulation of bone remodeling, was restored to a level similar to that observed in normal B6 mice. Furthermore, the message level of IL-6, which is known to enhance osteoclastogenesis, was also restored to normal. These results indicate that the BM microenvironment was normalized after IBM-BMT and that the increased production of IL-11 and IL-6 ameliorated the imbalance between bone absorption and formation, resulting in the prevention of osteoporosis in SAMP6 mice.

Donor cell–derived osteopoiesis originates from a self-renewing stem cell with a limited regenerative contribution after transplantation

“…25 Finally, transplantation of bone marrow cells in a murine model of a severe genetically linked osteoporosis was followed by rapid amelioration of the pathologic phenotype with a slow reversion to the pretreatment status over time. 26,27 How, then, does one explain high levels of osteopoietic engraftment early after BMT with diminishing osteopoietic chimerism over time? Bone is a dynamic tissue undergoing continuous remodeling with high cell and matrix turnover.…”

Analyses of Very Early Hemopoietic Regeneration After Bone Marrow Transplantation: Comparison of Intravenous and Intrabone Marrow Routes

“…In fact, we and others have documented the remarkable advantages of intrabone-marrow (IBM)-BMT over intravenous (IV)-BMT in refractory BMT settings, such as [normal3 MRL/lpr mice] [8] and [human BMCs3 SCID mice] [3,4,9]. Moreover, we have found recently that senile osteoporosis in SAMP6 mice can be prevented and treated effectively by IBM-BMT using BMC from healthy mice [10,11]. In the recipient mice, the proliferation of donor stromal cells was also observed at the site of injection [8,11].…”

New strategies for allogeneic BMT

“…In addition, we have found that IBM-BMT can be used to prevent and treat osteoporosis in SAMP6 mice. 15 We therefore believe that this method (IBM-BMT in conjunction with the Perfusion Method) will become a powerful new strategy for the treatment of various intractable diseases. Furthermore, we believe that this method will become a valuable strategy in regeneration therapy for injured organs and tissues (osteoporosis, emphysema, myocardial infarction, cerebral infarction, Alzheimer's disease, etc), since IBM-BMT can efficiently reconstitute the recipient with both donor-derived hemopoietic stem cells and MSCs.…”