Gene-metabolite networks associated with impediment of bone fracture repair in spaceflight

Nabarun Chakraborty; Ariane Zamarioli; Aarti Gautam; Ross Campbell; Stephen K Mendenhall; Paul J Childress; George Dimitrov; Bintu Sowe; Aamir Tucker; Liming Zhao; Rasha Hammamieh; Melissa A Kacena

doi:10.1016/j.csbj.2021.05.050

Gene-metabolite networks associated with impediment of bone fracture repair in spaceflight

Comput Struct Biotechnol J. 2021 Jun 8:19:3507-3520. doi: 10.1016/j.csbj.2021.05.050. eCollection 2021.

Authors

Nabarun Chakraborty¹, Ariane Zamarioli^{2

3}, Aarti Gautam¹, Ross Campbell^{1

4}, Stephen K Mendenhall⁵, Paul J Childress², George Dimitrov^{1

4}, Bintu Sowe^{2

6}, Aamir Tucker², Liming Zhao², Rasha Hammamieh¹, Melissa A Kacena^{2

7}

Affiliations

¹ Medical Readiness Systems Biology, CMPN, WRAIR, Silver Spring, MD, USA.
² Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
³ Department of Orthopaedics and Anaesthesiology, Ribeirão Preto Medical School, SP, Brazil.
⁴ Geneva Foundation, Medical Readiness Systems Biology, CMPN, WRAIR, Silver Spring, MD, USA.
⁵ Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ ORISE, Medical Readiness Systems Biology, CMPN, WRAIR, Silver Spring, MD, USA.
⁷ Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.

Abstract

Adverse effects of spaceflight on musculoskeletal health increase the risk of bone injury and impairment of fracture healing. Its yet elusive molecular comprehension warrants immediate attention, since space travel is becoming more frequent. Here we examined the effects of spaceflight on bone fracture healing using a 2 mm femoral segmental bone defect (SBD) model. Forty, 9-week-old, male C57BL/6J mice were randomized into 4 groups: 1) Sham surgery on Ground (G-Sham); 2) Sham surgery housed in Spaceflight (FLT-Sham); 3) SBD surgery on Ground (G-Surgery); and 4) SBD surgery housed in Spaceflight (FLT-Surgery). Surgery procedures occurred 4 days prior to launch; post-launch, the spaceflight mice were house in the rodent habitats on the International Space Station (ISS) for approximately 4 weeks before euthanasia. Mice remaining on the Earth were subjected to identical housing and experimental conditions. The right femur from half of the spaceflight and ground groups was investigated by micro-computed tomography (µCT). In the remaining mice, the callus regions from surgery groups and corresponding femoral segments in sham mice were probed by global transcriptomic and metabolomic assays. µCT confirmed escalated bone loss in FLT-Sham compared to G-Sham mice. Comparing to their respective on-ground counterparts, the morbidity gene-network signal was inhibited in sham spaceflight mice but activated in the spaceflight callus. µCT analyses of spaceflight callus revealed increased trabecular spacing and decreased trabecular connectivity. Activated apoptotic signals in spaceflight callus were synchronized with inhibited cell migration signals that potentially hindered the wound site to recruit growth factors. A major pro-apoptotic and anti-migration gene network, namely the RANK-NFκB axis, emerged as the central node in spaceflight callus. Concluding, spaceflight suppressed a unique biomolecular mechanism in callus tissue to facilitate a failed regeneration, which merits a customized intervention strategy.

Keywords: Bone; Bone defect; Gene-metabolite network; Genomics; Metabolomics; Mouse model; Space.