1,25(OH)2D3 inhibits bone marrow adipogenesis in senescence accelerated mice (SAM-P/6) by decreasing the expression of peroxisome proliferator-activated receptor gamma 2 (PPARγ2)

Abstract

Senile osteoporosis is the endpoint of a continuum that starts after the third decade of life when peak bone mass is attained and then is followed by a progressive and irreversible decline in bone mass. One of the mechanisms that could explain this is the increasing levels of adipogenesis in bone marrow seen with increasing age, probably due to alterations in the differentiation of mesenchymal stem cells (MSC). Senescence accelerated mice (SAM-P/6) constitute an accepted model for senile osteoporosis since their loss of bone mineral density is clearly due to high levels of adipogenesis and a deficit in osteoblastogenesis. It is known that MSC expressing a ligand-activated transcription factor known as peroxisome proliferators-activated receptor gamma 2 (PPARγ2) are committed to differentiate into adipocytes. The regulation of PPARγ2 activation may play a role in the control of adipogenic differentiation of MSC and thus contribute to their differentiation into osteoblasts in order to form new bone. Our previous studies have shown that the active form of vitamin D (1,25(OH)2D3) plays a role as a bone forming agent because it induces osteoblastogenesis and inhibits adipogenesis in bone marrow of SAM-P/6 mice. To elucidate the role of 1,25(OH)2D3 on the expression of PPARγ2 we treated 4-month old SAM-P/6 mice with 1,25(OH)2D3 (18pmol/24 h) or vehicle during 6 weeks. Initially we found that with aging the levels of PPARγ2 expression increase in bone marrow of SAM-P/6 (p<0.001). We then measured the changes in the expression of PPARγ2 by semi-quantitative reverse transcription-polymerase chain reaction and immunofluorescence. We found a significant reduction of PPARγ2-expressing cells in 1,25(OH)2D3-treated (32% ±6) as compared to vehicle (76% ±5) treated mice (p<0.01). In summary, this study shows that the administration of 1,25(OH)2D3 in an in vivo model of senile osteoporosis is associated with reduction in PPARγ2 a key transcription factor for the adipose differentiation of MSC. © 2003 Elsevier Inc. All rights reserved.