A New Concept Underlying Stem Cell Lineage Skewing That Explains the Detrimental Effects of Thiazolidinediones on Bone

Abstract

Bone-marrow adipogenesis is an aging-related phenomenon and is correlated with osteoporosis. The latter is a prevalent bone disease in the elderly leading to increased fracture risk and mortality. It is widely hypothesized that the underlying molecular mechanism includes a shift in the commitment of mesenchymal stem cells (MSCs) from the osteogenic lineage to the adipogenic lineage. Lineage skewing is at least partially a result of transcriptional changes. The nuclear transcription factor peroxisome proliferator-activated receptor c (PPAR-c) has been proposed as a major decision factor in MSC lineage commitment, promoting adipogenesis at the expense of osteogenesis. Here we found that PPAR-c acted unexpectedly to stimulate osteoblast differentiation from human bone marrowderived MSCs. Both rosiglitazone-mediated activation and overexpression of PPAR-c caused acceleration of osteoblast differentiation. Conversely, shRNAi-mediated PPARc knockdown diminished osteoblast differentiation. MSCs that were treated with rosiglitazone did not preferentially differentiate into adipocytes. However, the rosiglitazonemediated acceleration of osteoblast differentiation was followed by increased accumulation of reactive oxygen species and apoptosis. In contrast to the osteogenic lineage, cells of the adipogenic lineage were protected from this. Our data support a new concept on bone health that adds to the explanation of the clinically observed suppressive action of activated PPAR-c on bone and the associated phenomenon of bone marrow adipogenesis. This concept is based on a higher susceptibility of the osteogenic than the adipogenic lineage to oxidative stress and apoptosis that is preferentially triggered in the osteoblasts by activated PPAR-c. STEM CELLS 2010;28:916-927 Disclosure of potential conflicts of interest is found at the end of this article.

The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis

“…PPAR-γ has been shown in preclinical studies to promote the differentiation of mesenchymal stem cells into adipocytes rather than osteoblasts [46], and to promote osteoclast differentiation and increase osteoclast numbers [45]. In addition, exposure to TZDs appears to induce osteoblast and osteocyte apoptosis [47][48][49]. A reduction in the number of osteocytes and osteoblasts has the potential for prolonged negative effects on bone, given the relatively long differentiation periods and lifespans of these cell types [50].…”

Pathophysiological role of enhanced bone marrow adipogenesis in diabetic complications

“…128,129 It has also been proposed that rosiglitazone is able to accelerate both fat and bone cell maturation through the PPARg2 isoform in adipocytes and PPARg1 in osteoblasts, with a substantial build-up of ROS. 130 Yet, others have reported that induction of adipogenesis through PPARg stimulation does, in fact, necessarily reduce osteoblast differentiation and function, supporting the notion of a shared pool of progenitor cells. 123,[131][132][133] A number of prospective and retrospective observational investigations have aimed to determine whether TZD use is associated with a negative effect on bone density in humans.…”

MANAGEMENT OF ENDOCRINE DISEASE: Diabetes and osteoporosis: cause for concern?

“…The use of thiazolidinediones (glitazones) may lead to bone loss (49) and more fractures (50), because stem cells preferentially differentiate into adipocytes rather than osteoblasts (51,52,53).…”