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The hindlimb unloading (HU) rodent model is used to mimic changes incurred in spaceflight due to microgravity. Previously in 2‐weeks of rat HU, we found systemically impaired lymphatic transport. Recently we reported gastrointestinal (GI) inflammation and lymphatic immune cell alterations after 4‐weeks of HU in rats paralleling the GI pathology observed in inflammatory bowel disease (IBD) animal models. A known comorbidity of IBD is inflammation‐induced bone loss; prior work in our lab with a 4‐week IBD rodent model documented bone loss as well as an increased prevalence of cancellous osteocytes positive for tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and insulin‐like growth factor‐I (IGF‐I) concurrent with GI inflammation. The implications of a potential inflammatory link between gut and bone in HU and spaceflight have not been reported. In this study we quantified TNF‐α, IL‐6, and IGF‐I (via immunohistochemistry) in both bone and colon samples after 4‐weeks of HU in male Sprague Dawley rats (comparing HU and age‐matched controls). Proximal tibia cancellous bone volume, osteoid surface area, bone formation rate, and trabecular number were lower in HU versus controls, while osteoclast surface area and trabecular separation were higher. Measures of osteocytes in cancellous bone positive for IL‐6 and IGF‐I levels were lowered, but there was no change in TNF‐α. Colon histopathology showed elevated structural damage in the mucosa region with a corresponding cellularity elevation in HU compared to controls. HU colons also had elevated TNF‐α and IL‐6 expression across the mucosal and submucosal regions with IGF‐I a trending increase. Furthermore cytokine changes were dependent on the colon compartment. Fecal calprotectin (a clinical IBD marker of GI inflammation) was collected throughout the 4‐week time course; calprotectin was significantly increased at 2‐weeks of HU and trended towards elevation at 4‐weeks. After HU we did not find the same cytokine pattern in bone compared to what we have seen in an IBD model induced by the haptenizing agent TNBS, suggesting different inflammatory mechanisms. However there may be a time course impact of IBD development in the models.Support or Funding InformationStudy support received from NASA Grants: NNX15AG54G, NNX13AN33G, NNX13AQ87G. AN, JB, and SL were supported by the NASA‐NSBRI Predoctoral Fellowship.

BACKGROUND: The impact of the spaceflight environment on endogenous estrogen production in female crewmembers and the resulting impact on other adaptations, like bone loss, is an under-investigated topic. Hence, we investigated the interaction of exogenous 17- estradiol (E2) treatment and disuse to test the hypothesis that E2 treatment would mitigate disuse-induced bone loss.METHODS: There were 40 virgin female Sprague-Dawley rats (5 mo old) randomized to placebo (PL; 0 ppm E2) or estrogen (E2; 10 ppm E2) treatments, delivered via custom-made rodent diets; half of each group was randomized to either weightbearing (WB) or hindlimb unloading (HU) for 39 d.RESULTS: We observed expected lower values after HU (615%) in volumetric BMD and cross-sectional areas at the proximal tibia metaphysis (PTM, by pQCT), 20% lower %BV/TV (nonsignificant) at the PTM, and 11% lower femoral neck maximal load; none of these HU-induced impacts were modified by E2. Impaired PTM periosteal expansion was observed in all E2-treated rats, with smaller (13 to 18%) cross-sectional areas. Midshaft tibial geometry was unaffected by E2 treatment, but large reductions (73 to 81%) in periosteal bone formation indices were observed in E2-treated rats.DISCUSSION: In summary, modest supplementation of exogenous E2 did not mitigate decrements in volumetric BMD, PTM cross-sectional geometry, or femoral neck strength observed with HU. However, numerous independent impacts of E2 treatment were observed, with significant suppression of periosteal bone formation indices. If maintained over time, this might impact negatively on cortical bone integrity during prolonged nonweightbearing.Mantri AV, Allaway HCM, Brezicha JE, Hogan HA, Bloomfield SA. Oral estradiol impact on mitigating unloading-induced bone loss in ovary-intact rats. Aerosp Med Hum Perform. 2021; 92(2):6574.

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