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New Surgical Model for Bone-Muscle Injury Reveals Age and Gender-Related Healing Patterns in the 5 Lipoxygenase (5LO) Knockout Mouse

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Biguetti, Claudia Cristina [1, 2] ; Rondina Couto, Maira Cristina [3, 4] ; Rodrigues Silva, Ana Claudia [1] ; Tadashi Cosin Shindo, Joao Vitor [4] ; Rosa, Vinicius Mateus [1] ; Shinohara, Andre Luis [4] ; Andreo, Jesus Carlos [4] ; Hungaro Duarte, Marco Antonio [4] ; Wang, Zhiying [2] ; Brotto, Marco [2] ; Matsumoto, Mariza Akemi [1]
Número total de Autores: 11
Afiliação do(s) autor(es):
[1] Sao Paulo State Univ UNESP, Sch Dent, Dept Basic Sci, Aracatuba - Brazil
[2] Univ Texas Arlington, Bone Muscle Res Ctr, Coll Nursing & Hlth Innovat, Arlington, TX 76019 - USA
[3] Univ Sagrado Coracao, Dept Hlth Sci, Bauru, SP - Brazil
[4] Univ Sao Paulo, Bauru Sch Dent, FOB USP, Sao Paulo - Brazil
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Citações Web of Science: 0

Signaling lipid mediators released from 5 lipoxygenase (5LO) pathways influence both bone and muscle cells, interfering in their proliferation and differentiation capacities. A major limitation to studying inflammatory signaling pathways in bone and muscle healing is the inadequacy of available animal models. We developed a surgical injury model in thevastus lateralis(VL) muscle and femur in 129/SvEv littermates mice to study simultaneous musculoskeletal (MSK) healing in male and female, young (3 months) and aged (18 months) WT mice compared to mice lacking 5LO (5LOKO). MSK defects were surgically created using a 1-mm punch device in the VA muscle followed by a 0.5-mm round defect in the femur. After days 7 and 14 post-surgery, the specimens were removed for microtomography (microCT), histopathology, and immunohistochemistry analyses. In addition, non-injured control skeletal muscles along with femur and L5 vertebrae were analyzed. Bones were microCT phenotyped, revealing that aged female WT mice presented reduced BV/TV and trabecular parameters compared to aged males and aged female 5LOKO mice. Skeletal muscles underwent a customized targeted lipidomics investigation for profiling and quantification of lipid signaling mediators (LMs), evidencing age, and gender related-differences in aged female 5LOKO mice compared to matched WT. Histological analysis revealed a suitable bone-healing process with osteoid deposition at day 7 post-surgery, followed by woven bone at day 14 post-surgery, observed in all young mice. Aged WT females displayed increased inflammatory response at day 7 post-surgery, delayed bone matrix maturation, and increased TRAP immunolabeling at day 14 post-surgery compared to 5LOKO females. Skeletal muscles of aged animals showed higher levels of inflammation in comparison to young controls at day 14 post-surgery; however, inflammatory process was attenuated in aged 5LOKO mice compared to aged WT. In conclusion, this new model shows that MSK healing is influenced by age, gender, and the 5LO pathway, which might serve as a potential target to investigate therapeutic interventions and age-related MSK diseases. Our new model is suitable for bone-muscle crosstalk studies. (AU)

Processo FAPESP: 18/19406-0 - Papel da enzima 5-lipoxigenase (5-LO) sobre o fenótipo de ossos de origem intramembranosa e endocondral: anatomia macroscópica e microscópica comparativa entre camundongos 129/Sv-WT e 129/Sv 5-LOKO
Beneficiário:Ana Claudia Rodrigues da Silva
Linha de fomento: Bolsas no Brasil - Iniciação Científica
Processo FAPESP: 13/04714-8 - Efeito do chá verde no processo de reparo alveolar de ratos tratados com bifosfonato
Beneficiário:Mariza Akemi Matsumoto
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 18/08913-9 - Papel da enzima 5-lipoxigenase (5-LO) sobre o sistema musculoesquelético: análise comparativa do processo de reparo e processo de senescência do tecido ósseo e muscular em camundongos 129/Sv-WT e 129/Sv 5-LOKO
Beneficiário:Claudia Cristina Biguetti
Linha de fomento: Bolsas no Brasil - Pós-Doutorado