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Smoking Alters Inflammation and Skeletal Stem and Progenitor Cell Activity During Fracture Healing in Different Murine Strains
Authors:Zichen Hao  Jun Li  Bo Li  Kareme D Alder  Sean V Cahill  Alana M Munger  Inkyu Lee  Hyuk-Kwon Kwon  JungHo Back  Shuogui Xu  Min-Jong Kang  Francis Y Lee
Affiliation:1. Department of Orthopaedics and Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA;2. Department of Orthopaedics and Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA

Department of Orthopaedics, The Second Hospital of Anhui Medical University, Hefei, China

Contribution: Data curation, Formal analysis, ​Investigation, Methodology;3. Department of Orthopaedics and Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA

Department of Orthopaedics, Guizhou Provincial People's Hospital, Guiyang, China

Contribution: Data curation, Formal analysis, ​Investigation, Methodology;4. Department of Orthopaedics and Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA

Contribution: Data curation, Formal analysis, Writing - original draft, Writing - review & editing;5. Department of Orthopaedics and Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA

Contribution: Data curation, Formal analysis, ​Investigation, Writing - review & editing;6. Department of Orthopaedics and Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA

Contribution: Formal analysis, Writing - review & editing;7. Department of Orthopaedics and Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA

Department of Life Science, Chung-Ang University, Seoul, Republic of Korea

Contribution: Data curation, Formal analysis, ​Investigation;8. Department of Orthopaedics and Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA

Contribution: Formal analysis, ​Investigation;9. Department of Orthopaedics and Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA

Contribution: Conceptualization, Data curation, Formal analysis, ​Investigation, Methodology, Supervision, Validation, Visualization;10. Department of Emergency and Trauma, Changhai Hospital, Navy Medical University, Shanghai, China;11. Department of Medicine, Pulmonary, Critical Care, and Sleep Medicine, Yale University, School of Medicine, New Haven, CT, USA

Abstract:Smokers are at a higher risk of delayed union or nonunion after fracture repair. Few specific interventions are available for prevention because the molecular mechanisms that result in these negative sequelae are poorly understood. Murine models that mimic fracture healing in smokers are crucial in further understanding the local cellular and molecular alterations during fracture healing caused by smoking. We exposed three murine strains, C57BL/6J, 129X1/SvJ, and BALB/cJ, to cigarette smoke for 3 months before the induction of a midshaft transverse femoral osteotomy. We evaluated fracture healing 4 weeks after the osteotomy using radiography, micro-computed tomography (μCT), and biomechanical testing. Radiographic analysis demonstrated a significant decrease in the fracture healing capacity of smoking 129X1/SvJ mice. μCT results showed delayed remodeling of fracture calluses in all three strains after cigarette smoke exposure. Biomechanical testing indicated the most significant impairment in the functional properties of 129X1/SvJ in comparison with C57BL/6J and BALB/cJ mice after cigarette smoke exposure. Thus, the 129X1/SvJ strain is most suitable in simulating smoking-induced impaired fracture healing. Furthermore, in smoking 129X1/SvJ murine models, we investigated the molecular and cellular alterations in fracture healing caused by cigarette smoking using histology, flow cytometry, and multiplex cytokine/chemokine analysis. Histological analysis showed impaired chondrogenesis in cigarette smoking. In addition, the important reparative cell populations, including skeletal stem cells and their downstream progenitors, demonstrated decreased expansion after injury as a result of cigarette smoking. Moreover, significantly increased pro-inflammatory mediators and the recruitment of immune cells in fracture hematomas were demonstrated in smoking mice. Collectively, our findings demonstrate the significant cellular and molecular alterations during fracture healing impaired by smoking, including disrupted chondrogenesis, aberrant skeletal stem and progenitor cell activity, and a pronounced initial inflammatory response. © 2020 American Society for Bone and Mineral Research (ASBMR).
Keywords:CIGARETTE SMOKING  FRACTURE HEALING  INFLAMMATORY RESPONSE  MURINE MODELS  SKELETAL STEM/PROGENITOR CELLS
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