Spaceflight-Relevant Challenges of Radiation and/or Reduced Weight Bearing Cause Arthritic Responses in Knee Articular Cartilage

Abstract

There is little known about the effect of both reduced weight bearing and exposure to radiation during spaceflight on the mechanically-sensitive cartilage lining the knee joint. In this study, we characterized cartilage damage in rat knees after periods of reduced weight bearing with/without exposure to solar-flare-relevant radiation, then cartilage recovery after return to weight bearing. Male Sprague Dawley rats (n = 120) were either hindlimb unloaded (HLU) via tail suspension or remained weight bearing in cages (GROUND). On day 5, half of the HLU and GROUND rats were 1 Gy total-body X-ray irradiated during HLU, and half were sham irradiated (SHAM), yielding 4 groups: GROUND-SHAM; GROUND-IR; HLU-SHAM; and HLU-IR. Hindlimbs were collected from half of each group of rats on day 13. The remaining rats were then removed from HLU or remained weight bearing, and hindlimbs from these rats were collected on day 62. On day 13, glycosaminoglycan (GAG) content in cartilage lining the tibial plateau and femoral condyles of HLU rats was lower than that of the GROUND animals. Likewise, on day 13, immunoreactivity of the collagen type II-degrading matrix metalloproteinase-13 (MMP-13) and of a resultant metalloproteinase-generated neoepitope VDIPEN was increased in all groups versus GROUND-SHAM. Clustering of chondrocytes indicating cartilage damage was present in all HLU and IR groups versus GROUND-SHAM on day 13. On day 62, after 49 days of reloading, the loss of GAG content was attenuated in the HLU-SHAM and HLU-IR groups, and the increased VDIPEN staining in all treatment groups was attenuated. However, the increased chondrocyte clustering remained in all treatment groups on day 62. MMP-13 activity also remained elevated in the GROUND-IR and HLU-IR groups. Increased T2 relaxation times, measured on day 62 using 7T MRI, were greater in GROUND-IR and HLU-IR knees, indicating persistent cartilage damage in the irradiated groups. Both HLU and total-body irradiation resulted in acute degenerative and pre-arthritic changes in the knee articular cartilage of rats. A return to normal weight bearing resulted in some recovery from cartilage degradation. However, radiation delivered as both a single challenge and when combined with HLU resulted in chronic cartilage damage. These findings suggest that radiation exposure during spaceflight leads to and/or impairs recovery of cartilage upon return to reloading, generating long-term joint problems for astronauts.

Knee and Hip Joint Cartilage Damage from Combined Spaceflight Hazards of Low-Dose Radiation Less than 1 Gy and Prolonged Hindlimb Unloading

“…Joint loading on Earth is necessary to maintain structural integrity, proper function and homeostasis of cartilage and other tissues constituting load-bearing synovial joints (1,2). Thus, the reduced weight bearing experienced with spaceflight represents a substantial challenge to maintaining the health of synovial joints (3)(4)(5)(6). Clinically relevant structural degradation of cartilage has been documented after periods of prescribed partial-or nonweight-bearing (3)(4)(5).…”

Cartilage breakdown in microgravity—a problem for long-term spaceflight?

“…A recent report suggesting that radiation worsens cartilage loss caused by HLU suggests that radiation has a compounding effect on cartilage destruction. 10 …”

Exposure to hypergravity during zebrafish development alters cartilage material properties and strain distribution

“…This cartilage has a limited regenerative capacity (Karuppal, 2017) and is important for absorbing load to protect the underlying bone, ensuring the smooth function of joints (Fox, Bedi and Rodeo, 2009). Human bed-rest studies, hind-limb unloading studies in rats and studies performed on mice exposed to real microgravity have demonstrated that loss of mechanical forces lead to cartilage degradation primarily through proteoglycan loss (Souza et al , 2012; Ganse et al , 2015; Willey et al , 2016; Fitzgerald et al , 2019). Cell culture experiments carried out in microgravity also support the observation of cartilage degradation under reduced loading conditions, with cytoskeletal reorganization and extracellular matrix (ECM) composition altered following short exposures (Van Loon et al , 1995; Freed et al , 1997; Zhang et al , 2003; Ulbrich et al , 2010; Aleshcheva et al , 2013).…”