Abstract
Background
Type 2 diabetes mellitus (T2DM) afflicts about six percent of the global population,
and these patients suffer from a two-fold increased fracture risk. Thiazolidinediones
(TZDs), including rosiglitazone, are commonly used medications in T2DM because they
have a low incidence of monotherapy failure. It is known that rosiglitazone is associated
with secondary osteoporosis, further increasing the fracture risk in an already susceptible
population. However, it is not yet understood how rosiglitazone impacts endochondral
bone healing after fracture. The aim of this study is to elucidate how rosiglitazone
treatment impacts endochondral fracture healing, and how rosiglitazone influences
the differentiation of skeletal stem and progenitor cells from the bone marrow and
the periosteum.
Methods
An in-vivo mouse femur fracture model was employed to evaluate differences in fracture healing
between mice treated with and without rosiglitazone chow. Fracture healing was assessed
with histology and micro computed tomography (μCT). In-vitro assays utilized isolated mouse bone marrow stromal cells and periosteal cells to
investigate how rosiglitazone impacts the osteogenic capability and adipogenicity
of these cells.
Results
The in-vivo mouse femur fracture model showed that fracture callus in mice treated with rosiglitazone
had significantly more adipose content than those of control mice that did not receive
rosiglitazone. In addition, μCT analysis showed that rosiglitazone treated mice had
significantly greater bone volume, but overall greater porosity when compared to control
mice. In-vitro experimentation showed significantly less osteogenesis and more adipogenesis in bone
marrow derived progenitor cells that were cultured in osteogenic media. In addition,
rosiglitazone treatment alone caused significant increases in adipogenesis in both
bone marrow and periosteum derived cells.
Conclusion
Rosiglitazone impairs endochondral fracture healing in mice by increasing adipogenesis
and decreasing osteogenesis of both bone marrow and periosteum derived skeletal progenitor
cells.
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References
- Epidemiology of type 2 diabetes - global burden of disease and forecasted trends.J Epidemiol Glob Health. 2020 Mar; 10: 107-111
- Risk of fracture in women with type 2 diabetes: the women's health initiative observational study.J Clin Endocrinol Metab. 2006 Sep; 91: 3404-3410
- Fate decision of mesenchymal stem cells: adipocytes or osteoblasts?.Cell Death Differ. 2016 Jul; 23: 1128-1139
- Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes.Diabetes Obes Metabol. 2010 Aug; 12: 716-721
- Pathophysiological role of enhanced bone marrow adipogenesis in diabetic complications.Adipocyte. 2014 Oct-Dec; 3: 263-272
- Rosiglitazone inhibits bone regeneration and causes significant accumulation of fat at sites of new bone formation.Calcif Tissue Int. 2012 Aug; 91: 139-148
- The effect of thiazolidinediones on bmd and osteoporosis.Nat Clin Pract Endocrinol Metabol. 2008 Sep; 4: 507-513
- The effects of thiazolidinediones on human bone marrow stromal cell differentiation in vitro and in thiazolidinedione-treated patients with type 2 diabetes.Transl Res. 2013 Mar; 161: 145-155
- Effects of thiazolidinediones on bone loss and fracture.Ann Pharmacother. 2007 Dec; 41: 2014-2018
- The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial.J Clin Endocrinol Metab. 2007 Apr; 92: 1305-1310
- The effects of rosiglitazone on osteoblastic differentiation, osteoclast formation and bone resorption.Mol Cell. 2012 Feb; 33: 173-181
- Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone.Endocrinology. 2007 Jun; 148: 2669-2680
- Effect of rosiglitazone on bone quality in a rat model of insulin resistance and osteoporosis.Diabetes. 2011 Dec; 60: 3271-3278
- Rosiglitazone promotes bone marrow adipogenesis to impair myelopoiesis under stress.PLoS One. 2016; 11e0149543
- Diabetes Outcome Progression Trial Study G. Rosiglitazone-associated fractures in type 2 diabetes: an analysis from a diabetes outcome progression trial (adopt).Diabetes Care. 2008 May; 31: 845-851
- Propranolol reverses impaired fracture healing response observed with selective serotonin reuptake inhibitor treatment.J Bone Miner Res. 2020 May; 35: 932-941
- Age-related inflammation triggers skeletal stem/progenitor cell dysfunction.Proc Natl Acad Sci U S A. 2019 Apr 2; 116: 6995-7004
- Effect of mechanical stimuli on skeletal regeneration around implants.Bone. 2007 Apr; 40: 919-930
- Guidelines for assessment of bone microstructure in rodents using micro-computed tomography.J Bone Miner Res. 2010 Jul; 25: 1468-1486
- A method for isolating high quality rna from mouse cortical and cancellous bone.Bone. 2014; 68 (2014-11-01): 1-5
- Hox gene expression determines cell fate of adult periosteal stem/progenitor cells.Sci Rep. 2019 Mar 25; 9: 5043
- Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus.J Clin Endocrinol Metab. 2013 Apr; 98: 1519-1528
- Mesenchymal stem cells in bone regeneration.Adv Wound Care. 2013 Jul; 2: 306-316
- Pioglitazone and risk for bone fracture: safety data from a randomized clinical trial.J Clin Endocrinol Metab. 2017 Mar 1; 102: 914-922
Article info
Publication history
Published online: December 06, 2021
Accepted:
November 10,
2021
Received in revised form:
October 21,
2021
Received:
April 9,
2021
Identification
Copyright
© 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.
