Diminished Chondrogenesis and Enhanced Osteoclastogenesis in Leptin-Deficient Diabetic Mice (ob/ob) Impair Pathologic, Trauma-Induced Heterotopic Ossification

Shailesh Agarwal, Shawn Loder, John Li, Cameron Brownley, Jonathan R. Peterson, Eboda Oluwatobi, James Drake, David Cholok, Kavitha Ranganathan, Hsiao Hsin Sung, James Goulet, Shuli Li, Benjamin Levi

Research output: Contribution to journalArticle

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 mm3, 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.

Original languageEnglish (US)
Pages (from-to)2864-2872
Number of pages9
JournalStem Cells and Development
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2015
Externally publishedYes

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Heterotopic Ossification
Chondrogenesis
Leptin
Osteogenesis
Wounds and Injuries
Bone Development
Osteoclasts
Tenotomy
Bone and Bones
Body Surface Area
Bone Resorption
Wound Healing
Type 2 Diabetes Mellitus
Cartilage
Real-Time Polymerase Chain Reaction
Coloring Agents
Extremities
Gene Expression
Growth

ASJC Scopus subject areas

  • Hematology
  • Developmental Biology
  • Cell Biology

Cite this

Diminished Chondrogenesis and Enhanced Osteoclastogenesis in Leptin-Deficient Diabetic Mice (ob/ob) Impair Pathologic, Trauma-Induced Heterotopic Ossification. / Agarwal, Shailesh; Loder, Shawn; Li, John; Brownley, Cameron; Peterson, Jonathan R.; Oluwatobi, Eboda; Drake, James; Cholok, David; Ranganathan, Kavitha; Sung, Hsiao Hsin; Goulet, James; Li, Shuli; Levi, Benjamin.

In: Stem Cells and Development, Vol. 24, No. 24, 15.12.2015, p. 2864-2872.

Research output: Contribution to journalArticle

Agarwal, S, Loder, S, Li, J, Brownley, C, Peterson, JR, Oluwatobi, E, Drake, J, Cholok, D, Ranganathan, K, Sung, HH, Goulet, J, Li, S & Levi, B 2015, 'Diminished Chondrogenesis and Enhanced Osteoclastogenesis in Leptin-Deficient Diabetic Mice (ob/ob) Impair Pathologic, Trauma-Induced Heterotopic Ossification', Stem Cells and Development, vol. 24, no. 24, pp. 2864-2872. https://doi.org/10.1089/scd.2015.0135
Agarwal, Shailesh ; Loder, Shawn ; Li, John ; Brownley, Cameron ; Peterson, Jonathan R. ; Oluwatobi, Eboda ; Drake, James ; Cholok, David ; Ranganathan, Kavitha ; Sung, Hsiao Hsin ; Goulet, James ; Li, Shuli ; Levi, Benjamin. / Diminished Chondrogenesis and Enhanced Osteoclastogenesis in Leptin-Deficient Diabetic Mice (ob/ob) Impair Pathologic, Trauma-Induced Heterotopic Ossification. In: Stem Cells and Development. 2015 ; Vol. 24, No. 24. pp. 2864-2872.
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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 mm3, 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.",
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