title: Diminished Chondrogenesis and Enhanced Osteoclastogenesis in Leptin-Deficient Diabetic Mice (ob/ob) Impair Pathologic, Trauma-Induced Heterotopic Ossification.
abstract: Diabetic trauma patients exhibit delayed postsurgical wound, bony healing, and dysregulated bone development. However, the impact of diabetes on the pathologic development of ectopic bone or heterotopic ossification (HO) following trauma is unknown. In this study, we use leptin-deficient mice as a model for type 2 diabetes to understand how post-traumatic HO development may be affected by this disease process. Male leptin-deficient (ob/ob) or wild-type (C57BL/6 background) mice aged 6-8 weeks underwent 30% total body surface area burn injury with left hind limb Achilles tenotomy. Micro-CT (μCT) imaging showed significantly lower HO volumes in diabetic mice compared with wild-type controls (0.70 vs. 7.02 mm(3), P < 0.01) 9 weeks after trauma. Ob/ob mice showed evidence of HO resorption between weeks 5 and 9. Quantitative real time PCR (qRT-PCR) demonstrated high Vegfa levels in ob/ob mice, which was followed by disorganized vessel growth at 7 weeks. We noted diminished chondrogenic gene expression (SOX9) and diminished cartilage formation at 5 days and 3 weeks, respectively. Tartrate-resistant acid phosphatase stain showed increased osteoclast presence in normal native bone and pathologic ectopic bone in ob/ob mice. Our findings suggest that early diminished HO in ob/ob mice is related to diminished chondrogenic differentiation, while later bone resorption is related to osteoclast presence.
authors.affiliation: Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
authors.forename: Shailesh
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
authors.forename: Shawn
authors.initials: S
authors.lastname: Loder
authors.affiliation: Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
authors.forename: John
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
authors.forename: Cameron
authors.initials: C
authors.lastname: Brownley
authors.affiliation: Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Peterson
authors.affiliation: Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
authors.forename: Eboda
authors.initials: E
authors.lastname: Oluwatobi
authors.affiliation: Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
authors.forename: James
authors.initials: J
authors.lastname: Drake
authors.affiliation: Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
authors.forename: David
authors.initials: D
authors.lastname: Cholok
authors.affiliation: Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Ranganathan
authors.affiliation: Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
authors.forename: Hsiao Hsin
authors.initials: HH
authors.lastname: Sung
authors.affiliation: Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
authors.forename: James
authors.initials: J
authors.lastname: Goulet
authors.affiliation: Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
authors.forename: Shuli
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Michigan Health System , Ann Arbor, Michigan.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Levi
mesh_terms: D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000293:injuries; D002478:Cells, Cultured; D020219:Chondrogenesis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology*; D020738:Leptin / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009999:Ossification, Heterotopic / Q000473:pathology*; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D020738:Leptin; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse