IRIG: Why TZD increases rate of bone fractures in diabetic individuals ?

01/13/2008 08:23
           TZD is a well-established insulin sensitizer that is widely used in clinics for the treatment of type 2 diabetes. Among the major side effects of TZD, increased rate for bone fractures has been known together with the side effects of TZD on CDV system. The molecular mechanism underlying the TZD-associated fracture is not clear. One possibility is that activation of PPARg by TZD inhibits the differentiation of osteoblasts that are required for bone formation. PPARg is known to inhibit differentiation of stem cells into osteoblasts and at meantime promotes differentiation of the stem cells into adipocytes. In response to PPARg activation, loss of esteoblasts will lead to less formation of bone materials, and thus bone fracture. However, this possibility is challenged by a study in “Nature Medicine”, in which an increase in bone absorption was found to be the reason for TZD-associated fracture. This point is demonstrated using tissue-specific PPARg knockout mice in which PPARg is removed in both endothelial cells and osteoclasts. Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. The PPARg-KO made the bone density much higher in the transgenic mice as bone-resorbtion was inhibited in the bone. This is a result of loss of osteoclasts. The study reveals that PPARg is required for osteoclast differentiation from the bone marrow cells. With normal PPARg expression in osteoblasts, the KO mice does not loss bone mass in response to TZD. Attached is the PDF file of this paper.
 
Merry Christmas!
 
By Jianping at PBRC

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Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm
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