Type 2 diabetic mice demonstrate slender long bones with increased fragility secondary to increased osteoclastogenesis.
Type 2 diabetics often demonstrate normal or increased bone mineral density, yet are at increased risk for bone fracture. Furthermore, the anti-diabetic oral thiazolidinediones (PPARgamma agonists) have recently been shown to increase bone fractures. To investigate the etiology of possible structural and/or material quality defects, we have utilized a well-described mouse model of Type 2 diabetes (MKR). MKR mice exhibit muscle hypoplasia from birth with reduced mass by the pre-diabetic age of 3 weeks. A compensatory hyperplasia ensues during early (5 weeks) development; by 6-8 weeks muscle is normal in structure and function. Adult whole-bone mechanical properties were determined by 4-point bending to test susceptibility to fracture. Micro-computed tomography and cortical bone histomorphometry were utilized to assess static and dynamic indices of structure, bone formation and resorption. Osteoclastogenesis assays were performed from bone marrow-derived non-adherent cells. The 8-week and 16-week, but not 3-week, male MKR had slender (i.e., narrow relative to length) femurs that were 20% weaker (p<0.05) relative to WT control femurs. Tissue-level mineral density was not affected. Impaired periosteal expansion during early diabetes resulted from 250% more, and 40% less of the cortical bone surface undergoing resorption and formation, respectively (p<0.05). Greater resorption persisted in adult MKR on both periosteal and endosteal surfaces. Differences were not limited to cortical bone as the distal femur metaphysis of 16 week MKR contained less trabecular bone and trabecular separation was greater than in WT by 60% (p<0.05). At all ages, MKR marrow-derived cultures demonstrated the ability for enhanced osteoclast differentiation in response to M-CSF and RANK-L. Taken together, the MKR mouse model suggests that skeletal fragility in Type 2 diabetes may arise from reduced transverse bone accrual and increased osteoclastogenesis during growth that is accelerated by the diabetic/hyperinsulinemic milieu. Further, these results emphasize the importance of evaluating diabetic bone based on morphology in addition to bone mass.
Kawashima
Yuki
Y
Division of Endocrinology, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA. yuki.kawashima@mssm.edu
Fritton
J Christopher
JC
Yakar
Shoshana
S
Epstein
Sol
S
Schaffler
Mitchell B
MB
Jepsen
Karl J
KJ
LeRoith
Derek
D
D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D001862:Bone Resorption / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology; D000071681:Tartrate-Resistant Acid Phosphatase; D055114:X-Ray Microtomography
D007527:Isoenzymes; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase