Spaceflight and hind limb unloading induces an arthritic phenotype in knee articular cartilage and menisci of rodents

Xiao W Mao,Raghunatha R Yammani,Ted A Bateman,Li Tan,Michael D Delp,Virginia L Ferguson,Jingyun Lee,Johannes F Plate,Louis S Stodieck,Cristina M Furdui,Joseph E Moore,Eric Livingston,Jeffrey S Willey,Mary L Bouxsein,Andy T Kwok,Bethany A Kerr,Samuel Rosas,Nequesha S Mohamed,David C Zawieja

doi:10.1038/s41598-021-90010-2

Abstract

Reduced knee weight-bearing from prescription or sedentary lifestyles are associated with cartilage degradation; effects on the meniscus are unclear. Rodents exposed to spaceflight or hind limb unloading (HLU) represent unique opportunities to evaluate this question. This study evaluated arthritic changes in the medial knee compartment that bears the highest loads across the knee after actual and simulated spaceflight, and recovery with subsequent full weight-bearing. Cartilage and meniscal degradation in mice were measured via microCT, histology, and proteomics and/or biochemically after: (1) ~ 35 days on the International Space Station (ISS); (2) 13-days aboard the Space Shuttle Atlantis; or (3) 30 days of HLU, followed by a 49-day weight-bearing readaptation with/without exercise. Cartilage degradation post-ISS and HLU occurred at similar spatial locations, the tibial-femoral cartilage-cartilage contact point, with meniscal volume decline. Cartilage and meniscal glycosaminoglycan content were decreased in unloaded mice, with elevated catabolic enzymes (e.g., matrix metalloproteinases), and elevated oxidative stress and catabolic molecular pathway responses in menisci. After the 13-day Shuttle flight, meniscal degradation was observed. During readaptation, recovery of cartilage volume and thickness occurred with exercise. Reduced weight-bearing from either spaceflight or HLU induced an arthritic phenotype in cartilage and menisci, and exercise promoted recovery.

Highlights

Reduced knee weight-bearing from prescription or sedentary lifestyles are associated with cartilage degradation; effects on the meniscus are unclear
As a comparative study for the International Space Station (ISS) investigation, we examined gross phenotypic and histologic changes in cartilage and menisci from age-matched male mice that were exposed to 30 days of reduced weight-bearing via hind limb unloading (HLU), followed by a 49 day readaptation portion that examined if running or climbing exercises could recover any cartilage and meniscal degradation that occurred from 30 days of HLU
The volume of the articular cartilage was lower after FLIGHT (− 15.4% vs ground controls (GC), p = 0.0033; − 15.8% vs vivarium controls (VIV); p = 0.0024) (Fig. 1c)

Summary

Introduction

Reduced knee weight-bearing from prescription or sedentary lifestyles are associated with cartilage degradation; effects on the meniscus are unclear. Short-term periods of HLU (13 days) in rats increases pro-arthritic biomarkers in knee cartilage, including matrix metalloproteinases (MMP), and loss of GAG content[19]. These responses are similar to elevated MMP-3 expression and lower GAG content in rat knees after 21 days of limb immobilization[20]. Longer periods of HLU (30 days) in female mice results in articular cartilage loss at the weight-bearing tibial-femoral cartilage contact point, increases MMP-13 concentration with associated decrease in collagen c oncentration[16], and alters signaling pathways associated with joint degradation in femoral head articular cartilage[16]. Further evaluation of microgravity on meniscus cells is necessary to understand the joint degradation that may occur during spaceflight, and the complex relationship these structures play in maintaining joint homeostasis

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