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. 2015 Mar;30(3):481-8.
doi: 10.1002/jbmr.2364.

An Insulin-Sensitizing Thiazolidinedione, Which Minimally Activates PPARγ, Does Not Cause Bone Loss

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Free PMC article

An Insulin-Sensitizing Thiazolidinedione, Which Minimally Activates PPARγ, Does Not Cause Bone Loss

Tomohiro Fukunaga et al. J Bone Miner Res. .
Free PMC article

Abstract

Rosiglitazone is an insulin-sensitizing thiazolidinedione (TZD) that activates the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). Although rosiglitazone effectively treats type II diabetes mellitus (T2DM), it carries substantial complications, including increased fracture risk. This predisposition to fracture is consistent with the fact that PPARγ preferentially promotes formation of adipocytes at the cost of osteoblasts. Rosiglitazone-activated PPARγ, however, also stimulates osteoclast formation. A new TZD analog with low affinity for binding and activation of PPARγ but whose insulin-sensitizing properties mirror those of rosiglitazone has been recently developed. Because of its therapeutic implications, we investigated the effects of this new TZD analog (MSDC-0602) on skeletal homeostasis, in vitro and in vivo. Confirming it activates the nuclear receptor in osteoclasts, rosiglitazone enhances expression of the PPARγ target gene, CD36. MSDC-0602, in contrast, minimally activates PPARγ and does not alter CD36 expression in the bone-resorptive cells. Consistent with this finding, rosiglitazone increases receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation and number, whereas MSDC-0602 fails to do so. To determine if this new TZD analog is bone sparing, in vivo, we fed adult male C57BL/6 mice MSDC-0602 or rosiglitazone. Six months of a rosiglitazone diet results in a 35% decrease in bone mass with increased number of osteoclasts, whereas that of MSDC-0602-fed mice is indistinguishable from control. Thus, PPARγ sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.

Keywords: BONE HISTOMORPHOMETRY; BONE µCT; OSTEOCLASTS; THIAZOLIDINEDIONE; TYPE II DIABETES MELLITUS.

Conflict of interest statement

Disclosures

JRC is the president and chief scientific officer of Metabolic Solutions Development Company. All other authors state that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
MSDC-0602 does not activate PPARγ. (A) BMMs were cultured in M-CSF and low-dose RANKL and treated with vehicle (DMSO) or TZDs for 5 days. CD36 was determined by qPCR. (B) BMMs were cultured in M-CSF and low-dose RANKL and treated with vehicle (DMSO) or TZDs for 5 days. The PPARγ co-activator, PGC-1β, was determined by qPCR. *p < 0.05 versus DMSO; #p < 0.05 versus MSDC-0602.
Fig. 2
Fig. 2
MSDC-0602 does not affect osteoclast differentiation. (A) BMMs were cultured in M-CSF and RANKL and treated with vehicle (DMSO) or TZDs for 5 days. The cells were stained for TRAP activity. Scale bars = 200 μm. (B) Quantitation of TRAP-expressing multinucleated cells (MNCs) (more than three nuclei per cell) generated from BMMs treated with vehicle or TZDs for 5 days. (C) BMMs were cultured in M-CSF and RANKL and treated with vehicle or TZDs for 5 days. Osteoclast differentiation markers β3 integrin subunit, cathepsin K, TRAP, and calcitonin receptor were determined by qPCR. **p < 0.01 versus DMSO; ##p < 0.01 versus MSDC-0602.
Fig. 3
Fig. 3
Effects of TZDs on food intake, body weight, insulin levels, and adiponectin expression. (A) Average food intake per mouse per day during experiment. (B) Average body weight measured at euthanization. (C) Average change of body weight. (D) Adiponectin mRNA in epididymal WAT measured at euthanization. (E) Serum insulin measured at euthanization. White bars = control; gray bars = rosiglitazone; black bars = MSDC-0602. **p < 0.01 versus control.
Fig. 4
Fig. 4
MSDC-0602 does not affect bone. Six-month-old mice were fed native chow or that supplemented with rosiglitazone or MSDC-0602. All determinations were made after 6 months. (A) Whole-body BMD. (B) μCT image of distal femur. (C) μCT determination of BV/TV, trabecular number, trabecular thickness, and trabecular separation of distal femoral. (D) TRAP-stained histological sections of proximal tibia of control, rosiglitazone-treated, and MSDC-0602-treated mice. (E) Histomorphometrically determined BV/TV, total number of osteoclasts normalized to bone surface (Oc.N/BS), the percentage of bone surface to which osteoclasts are juxtaposed (Oc.S/BS), and adipocyte number/field. (F–H) Mice were administered time-spaced courses of calcein and alizarin. Bone formation rate (BFR) and mineral apposition rate (MAR) were histomorphometrically quantitated. (I) Serum osteocalcin determination. White bars = control; gray bars = rosiglitazone; black bars = MSDC-0602. **p < 0.01 versus control; *p < 0.05 versus control; ##p < 0.01 versus rosiglitazone; #p < 0.05 versus <zaq;3>. Scale bars = 1 mm (B); 500 μm (D, top panels); 50 μm (D, bottom panels, and F).

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