Astronauts are exposed to prolonged periods of microgravity and high doses of radiation during spaceflight, which presents a significant physiological challenge to the human body. In the musculoskeletal system, it is known that lack of gravity results in muscle atrophy and bone density loss. However, the impact of spaceflight on cartilage integrity has not been well documented. Similar to bone and skeletal muscle tissue, articular cartilage of the synovial joints is constantly exposed to mechanical loading here on Earth. Although cartilage degradation is traditionally viewed as a wear and tear pathology caused by mechanical loads exceeding physiological conditions, it has also been shown that joint immobilization causes atrophy and degeneration of the articular cartilage. Progressive thinning of articular cartilage has been reported in both immobilized patients and unloaded animal models. Therefore cartilage integrity is highly regulated by biomechanical signals produced by physiological loads, however the molecular mechanisms involved in cartilage degradation during overuse and disuse are still elusive.
Overview
Crosstalk Between Subchondral Bone and Articular Cartilage in Reduced Gravity May Contribute to Catastrophic Joint Damage (Career Advancement Award)
Principal Investigator:
Liliana F. Mellor, Ph.D.
Organization:
North Carolina State University
Technical Summary
Osteoarthritis (OA) is the leading cause of disability in the US, and one of the few chronic diseases of aging without a cure. It is estimated that 30.3% of people ages 45-64, and 49.7% of people over 65 are diagnosed with arthritis. Osteoarthritis is not only characterized by cartilage degradation, but also by changes in subchondral bone thickness, osteophyte formation, synovial inflammation and degeneration of other soft tissues associated with the joint. It is also thought that interplay between the adjacent cartilage and subchondral bone tissues contribute to pathogenesis of OA. Aberrant crosstalk between signaling pathways in the two tissues may precipitate pathological conditions.
The goals of this study are to:
a) use an OA-induced animal model to investigate the effects of unloading on the onset and progression of osteoarthritis
b) to elucidate the molecular changes and signaling pathways involved in bone and articular cartilage degradation in response to reduced gravity, with specific assessment of possible interactions between these two adjacent tissues.
To our knowledge, this will be the first study to address the onset and progression of osteoarthritis in unloading conditions, and to investigate interactions between cartilage and subchondral bone in a reduced gravity environment. We will attempt to identify a common therapeutic target to prevent joint damage both during and after spaceflight, and to better address joint pathologies here on Earth.
It is known that unloading conditions results in rapid bone loss by up-regulation of sclerostin, a potent Wnt signaling inhibitor. We will use an unloading model to determine if bone loss contributes to cartilage degradation by comparing hind limb suspension (HLS) mice to ground controls. Further, in collaboration with Dr. Hank Donahue at Pennsylvania State University, we will also evaluate a sclerostin knockout mouse model (sost-/-) that does not exhibit bone loss in HLS. Using this approach, we will determine if microgravity alone can induce cartilage degradation and further investigate the effects of blocking sclerostin on cartilage integrity. We hypothesize that sost-/- mice in HLS will exhibit cartilage degradation, and that factors secreted from the degrading cartilage will affect the subchondral bone. In order to investigate if cartilage degradation can contribute to skeletal deterioration, we will use an induced-OA animal model and evaluate changes in both HLS and ground control specimens. This model will not only allow us to determine if cartilage degradation can induce bone damage, but will also allow us to investigate whether unloading conditions accelerate and/or aggravate cartilage degradation.
We hypothesize that lack of mechanical stimulation during unloading will result in more rapid cartilage degradation of both control and OA-induced animals when compared to their respective ground control groups, with the OA-induced unloaded model having the most drastic joint damage. Results obtained from this study will be relevant not only to the spaceflight environment, but also for prolonged bed rest and/or immobilization here on Earth. If our results support our hypothesis, we can deduce that crosstalk between cartilage and subchondral bone contributes to joint pathologies, and that sclerostin expression is indeed necessary to maintain cartilage health. Completion of this study will provide major advances in our understanding of tissue interactions between subchondral bone and articular cartilage in loading and unloading conditions, and the role of these interactions in joint degradation. We will test our hypothesis by successful completion of the following two specific aims:
Specific Aim 1: Using a murine HLS model, investigate how rapid bone loss (wild type) and no bone loss (sost-/-) affects articular cartilage integrity in unloading conditions. Evaluate the effects of sclerostin inhibition in articular cartilage degradation and joint pathologies.
Specific Aim 2: Using an OA-induced murine HLS model, determine if cartilage degradation affects subchondral bone architecture and integrity in both unloading and loaded conditions. Investigate whether unloading accelerates, or slows down, cartilage degradation.
Earth Applications
We will thoroughly investigate and determine whether degradation of one tissue results in greater degradation of the other adjacent tissue. Further, we will elucidate key signaling pathways involved in joint pathology resulting from unloading. Using that data, we can then identify potential therapeutic targets that will benefit both cartilage and subchondral bone health, and can help treat patients here on Earth with osteoporosis and osteoarthritis conditions.
This is the first study to integrate the interactions of articular cartilage and bone in spaceflight conditions to assess overall synovial joint integrity, and to investigate specific signaling pathways and mechanisms that result in bone resorption and cartilage degradation in unloading conditions. Results from this study will not only advance our knowledge of tissue interactions and joint integrity in a spaceflight environment, but will also help us elucidate the molecular mechanisms involved in cartilage degradation during immobilization and prolonged bed rest here on Earth. Understanding the mechanotransduction pathways involved in joint degradation during unloading conditions will be key to development of new therapeutic treatments to prevent joint damage during joint disuse.