Impact of microtrauma on the erythropoietic receptor of neuropathic Schwann cell-deficient mice

Dopke, Kelly M.1; Mansfield, Kirsten N.1; Tortora, Peter J.1; Koroneos, Zachary A.1; Manto, Kristen M.1; Ptasinski, Anna M.2; Stauch, Christopher M.3; King, Tonya S.1; Fanburg-Smith, Julie C.3,4,5; Hegarty, John P.3; Aynardi, Michael C.3; Elfar, John C.6

1Department of Orthopaedics, Penn State College of Medicine, Hershey, PA, USA

2Department of Orthopaedics, Allegheny General Hospital, Pittsburgh, PA, USA

3Department of Orthopaedics, Penn State Hershey Medical Center, Hershey, PA, USA

4Department of Pathology, Penn State Hershey Medical Center, Hershey, PA, USA

5Department of Pediatrics, Penn State Health, Hershey, PA, USA

6Department of Orthopaedics & Sports Medicine, University of Arizona, Tucson, AZ, USA

*Correspondence to: Kelly M. Dopke, kdopke@pennstatehealth.psu.edu.

Funding: This study was supported by a grant from American Orthopaedic Foot and Ankle Society, No. 150206.

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Regenerative Medicine Reports 1(1):p 106-115, September 2024. | DOI: 10.4103/RMR.REGENMED-D-23-00001

Abstract

Charcot neuropathic arthropathy is a degenerative disease commencing with vasculopathic peripheral neuropathy and progresses with repeated micro-trauma, leading to instability, collapse, and severe foot and ankle disruption. Prior work suggests that erythropoietin’s (EPO) anti-apoptotic and anti-inflammatory effects may be beneficial in functional recovery of traumatized limbs. Employing a validated murine model, we investigated if diet induced obese (DIO) EPO knockout mice experience accelerated neurodegenerative changes and if EPO administration blunts the degree of neurodegeneration compared with saline treatment and those lacking EPO receptors on Schwann cells. Sixteen wild-type (C57BL6) and 16 Schwann cell-deficient (MPZ Cre) mice were given a high fat diet, completed a 3-day EPO protocol, and began a 10-week treadmill regimen. Serum blood glucose levels were collected. None of the groups had elevated median blood glucoses. Sensory, radiographic, and histopathologic analysis demonstrated no evidence of Charcot neuropathic arthropathy. The neurodegenerative mouse model previously achieved was thus not replicated. While these genetically modified, knockout mice serve as suitable models for studying the impact of EPO on nerve crush injuries, the current study was unable to achieve neurodegeneration, as suggested by the lack of neuropathy. Furthermore, our DIO EPO group failed to demonstrate fundamental prerequisite phenotypic changes necessary in the establishment of a neurodegenerative mouse model. This model supports prior research by demonstrating that in the absence of DIO, repetitive traumatic insult alone does not induce neurodegenerative changes. Without these changes, researchers cannot appreciate differences between groups or observe interventions’ impact, such as EPO, on the development of neurodegeneration.

微创伤对许旺细胞缺失促红细胞生成素受体小鼠的影响

摘要

Charcot神经性关节病是一种退行性疾病，最早可见于血管病性周围神经病变，并伴有反复的微创伤，可导致不稳定、塌陷和严重的足部和脚踝损伤。既往研究表明，促红细胞生成素的抗细胞凋亡和抗炎作用可能有利于创伤肢体功能的恢复。因此，实验拟观察饮食诱导肥胖的促红细胞生成素敲除小鼠模型在是否经历了加速的神经退行性变化，以及与许旺细胞缺失促红细胞生成素受体的小鼠相比，促红细胞生成素是否可减缓神经退行性变化。为此，给予16只野生型C57BL6小鼠和16只许旺细胞中促红细胞生成素缺失型小鼠高脂肪饮食，而后进行为期3d的红细胞生成素治疗，并开始为期10周的跑步训练。血清血糖结果显示，各组小鼠的血糖未见显著升高；且感官、放射学和组织病理学分析均未见Charcot神经性关节病的证据。因此，没有成功复制神经退行性小鼠模型。虽然这些转基因敲除小鼠是研究红细胞生成素对神经挤压损伤影响的合适模型，但因为缺乏神经病变，因此目前的研究仍无法实现神经退行性变。此外，饮食性肥胖并红细胞生成素组未能证明建立神经退行性小鼠模型所需的必需表型变化。但是该模型仍支持了既往的研究，证明在没有饮食性肥胖时，单纯的重复创伤性损伤不会引起神经退行性变化。如果没有这些变化，就无法理解各组差异，也无法观察干预措施（如红细胞生成素）对神经退行性变发展的影响。