Rosiglitazone Causes Bone Loss in Mice by Suppressing Osteoblast Differentiation and Bone Formation

Abstract

Because osteoblasts and marrow adipocytes are derived from a common mesenchymal progenitor, increased adipogenesis may occur at the expense of osteoblasts, leading to bone loss. Our previous in vitro studies indicated that activation of the proadipogenic transcription factor peroxisome proliferator-activated receptor isoform gamma 2 with rosiglitazone suppressed osteoblast differentiation. Here, we show that 5-month-old Swiss-Webster mice receiving rosiglitazone for 28 d exhibited bone loss associated with an increase in marrow adipocytes, a decrease in the ratio of osteoblasts to osteoclasts, a reduction in bone formation rate, and a reduction in wall width--an index of the amount of bone formed by each team of osteoblasts. Rosiglitazone had no effect on the number of early osteoblast or osteoclast progenitors, or on osteoblast life span, but decreased the expression of the key osteoblastogenic transcription factors Runx2 and Osterix in cultures of marrow-derived mesenchymal progenitors. These effects were associated with diversion of bipotential progenitors from the osteoblast to the adipocyte lineage, and suppression of the differentiation of monopotential osteoblast progenitors. However, rosiglitazone had no effect on osteoblastic cells at later stages of differentiation. Hence, rosiglitazone attenuates osteoblast differentiation and thereby reduces bone formation rate in vivo, leading to bone loss. These findings provide a mechanistic explanation for the recent evidence that peroxisome proliferator-activated receptor isoform gamma activation is a negative regulator of bone mass and suggest that the increased production of oxidized fatty acids with age may indeed be an important mechanism for age-related osteoporosis in humans.

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

“…As mentioned earlier, osteoblast apoptosis increases with advancing age in mice [32]. Osteoblastogenesis also declines with age, perhaps due to diversion of the common progenitor toward the adipocyte lineage [23,125]. We have obtained preliminary evidence that the tonic suppression of bone formation by PPARγ increases with advancing age in mice as indicated by increased expression of Alox15 and PPARγ, as well as increased levels of oxidized lipid ligands of PPARγ [126].…”

“…Thus, PPARγ exerts a tonic suppressive effect on osteoblast differentiation and bone formation, most probably by diverting uncommitted progenitors into the adipocyte lineage at the expense of the osteoblast lineage. In support of this contention, mice given the PPARγ ligand rosiglitazone exhibited increased marrow adipogenesis and decreased osteoblastogenesis associated with decreased bone formation and bone loss [23].…”

Vanin-1 Pantetheinase Drives Increased Chondrogenic Potential of Mesenchymal Precursors in ank/ank Mice

“…For example, we have not yet tested if Vanin-1, as in other cells, 53 suppresses the expression and function in BMSCs and MSCs, of peroxisome proliferator-activated receptor ␥, a promoter of adipogenesis but suppressor of osteochondral differentiation in mesenchymal precursor cells. 54 We have not directly examined long-term effects of Vanin-1 gene knockout on phenotype and ank/ank mortality. 2 Last, because artery calcification is mild and is detected later than skeletal abnormalities in ank/ank mice, 13 we did not evaluate the effects of Vanin-1 deficiency on artery calcification in situ in ank/ank mice.…”

The association between thiazolidinediones and hospitalisation for fracture in type 2 diabetic patients: a Taiwanese population-based nested case–control study

“…Recent evidence has emerged that the widely used thiazolidinediones, oral hypoglycaemic agents known as insulin sensitisers that are often prescribed when other medications have failed to reduce blood glucose levels in patients with type 2 diabetes, may have a negative effect on the skeleton and increase the risk of fracture [2]. Since 2004, preclinical [3][4][5][6][7] and clinical studies [8][9][10] have indicated that thiazolidinediones use could alter bone metabolism, resulting in reduced osteoblastic bone formation and accelerated bone loss. As suggested by recent evidence from an epidemiological study [9] and a clinical trial [11], thiazolidinediones use is associated with a decrease in bone density in postmenopausal women.…”