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Overview

Assessment of Structural and Functional Knee Joint Degradation During Modeled Spaceflight

Principal Investigator:
Jeffrey S. Willey, Ph.D.

Organization:
Wake Forest School of Medicine

This project will study the risk of seriously damaging knee joints because of exposure to weightlessness and radiation during long duration spaceflights. The knee joint consists of articular cartilage lining bone, the meniscus which distributes forces through the joint, the ligaments joining bones, and the underlying bone. Maintaining health of all joint structures is necessary for proper knee function. Both exposure to space radiation and weightlessness during long spaceflights has the potential to damage these structures, increasing the risk of bone fracture or developing arthritis during spaceflight or after returning to earth. However, spaceflight effects on these tissues (besides bone) are largely unstudied.

To study this problem, we will remove the forces applied to the knees of rats through hind limb unloading. After determining how weightlessness can cause erosion of these structures, we will characterize how combined weightlessness and space radiation can damage the knee. Rats that have been exposed to weightlessness and/or radiation will be allowed to recover under normal weight-bearing conditions. Damage to and repair of the knee joint structures will be measured using noninvasive imaging techniques and stained tissue sections. We will identify proteins that are produced and can lead to joint tissue erosion during unloading radiation. Also, cells from the knee joint will be grown and their properties studied in tissue culture systems, further identifying the cause of knee joint damage.

Our goal is to determine the extent of and cause for knee joint damage during weightlessness and radiation characteristic of the spaceflight environment. Once we understand how the tissues in the knee are damaged during modeled spaceflight, we can develop and test ways to prevent this knee joint damage for future missions. We also will gain insights into how arthritis develops on earth, and how it can be prevented.


Technical Summary

Maintaining musculoskeletal health is a primary concern during long term spaceflights, and is crucial for ensuring both mission success and full skeletal recovery upon return to earth. The effects of unloading on knee joint soft tissue structures in the spaceflight environment are undefined, although clinical data suggests that joint degradation can occur quickly with reduced loading. These joint tissues include articular cartilage, menisci, and ligaments, which are crucial for proper joint function. Degradation of the knee joint during spaceflight may elevate the risk of subsequent bone fracture or arthritis. We hypothesize the health of the entire knee joint is critical to ensure musculoskeletal integrity during and after spaceflight.

This project addresses a currently undefined risk: joint damage during spaceflight. Our intent is to characterize whole knee joint damage following modeled spaceflight conditions (unloading and irradiation) using a rat model. Limited clinical and rodent data suggest degradation of knee joint articular cartilage, menisci, and ligaments occur within weeks of unloading. Our current research is revealing that radiation can induce rapid degradation of articular cartilage and menisci. To date, a thorough assessment of structural and strength changes across the whole joint, including the contribution of joint soft tissues to these changes under modeled spaceflight conditions, has not been conducted.

Our goals for this research project include:

1. Determine the time course for structural and strength degradation of the cartilage and menisci within the knee after combined exposure to unloading and irradiation.

2. Determine if recovery from degradation is possible after periods of reloading.

For our studies, rats will be divided into one of two groups: hind limb unloaded (HLU) or remain unsuspended in cages (GROUND). One week later, a cohort of HLU and GROUND rats (50% from each group) will receive a 1 Gy whole-body dose of X-rays (IR) from a clinical linear accelerator. We will characterize joint degradation resulting from HLU, IR, and HLU + IR after two weeks of suspension (1 week after IR), and then after 12 weeks of subsequent reloading. The following methods will be used to characterize structural, compositional, and strength changes in the knee joint using:

• T2 weighted maps generated from the 7 Tesla (7T) MRI

• Nanocomputed tomography (nano-CT)

• Whole joint histology

• Biochemical assays for meniscal and cartilage proteoglycan content

• Direct measurements of both compressive and viscoelastic properties of cartilage lining the knee joint.

Earth Applications

1. Radiation-therapy induced joint degradation. Joint degradation is often the major source of morbidity among cancer survivors who received radiation therapy during childhood. These adults are 54 times more likely than healthy siblings to have arthritis and require a joint replacement. Currently, no treatment for RT-induced joint degradation exists. Data suggests that radiation directly damages articular cartilage lining joints, causing i] an active release of glycosaminoglycans from articular cartilage, ii] reduced formation of articular cartilage, and iii] a weakening of the articular cartilage. To date, no in vivo rodent study of RT-induced cartilage damage has been performed. This NSBRI funded project will help characterize the extent and potential cause(s) for cartilage and joint degradation in vivo, which will be useful for the development and testing of therapeutics for radiation-therapy induced joint degradation.

2. Cartilage repair and reconstruction: Cartilage repair in the knee joint is often followed by a period of non-weight bearing that is thought to promote the healing response and maintain structural integrity of the repair. However, cartilage is a mechanically sensitive tissue and unloading of the knee joint may lead to degradation of the articular cartilage and surrounding tissues. Moreover, the catabolic response of the tissue in response to unloading could inhibit cartilage healing and global cartilage health. Our data will therefore provide insight into whether complete unloading of joints should be reconsidered as a strategy to promote healing after cartilage repair and reconstruction surgery.

This project's funding ended in 2014