The study of human aging has advanced considerably over the years, yielding new discoveries and methods for how we can mitigate the negative effects of natural aging over the course of one’s life. We now know that aging proceeds through only a handful of evolutionarily conserved biological processes that lead to changes in cellular and organ function, promoting a wide array of age-associated diseases, loss of resilience, frailty and ultimately death. Due to the many sources that ultimately can contribute to aging, interdisciplinary research approaches are becoming more popular, often focusing on a specific component of aging that can be applied to broader mechanisms of aging. The researchers at Brown’s Center on the Biology of Aging have adopted this approach and have made significant breakthroughs since the foundation of the Center.
Dr. Qian Chen joined Brown University in 2002 and is now the Michael G. Ehrlich, MD Endowed Chair in OrthopaedicResearch, Professor of Medical Science, and Vice Chair for Research in the Department of Orthopaedics at the Warren Alpert Medical School. He is also the director of the Center of Biomedical Research Excellence in Skeletal Health and Repair in Rhode Island Hospital, a multi-disciplinary translational research center established by the National Institutes of Health. Dr. Chen's group has made important research progress in cartilage and joint biology, focusing on osteoarthritis and potential interventions. His most recent paper, published in October 2020 (Liu et al., DOI: 10.1096/fj.202001448R), reveals novel mechanisms of osteoarthritis progression that suggest a multi-level involvement of growth factors in cartilage joint development and degradation. These findings could potentially harness an existing drug for treatment.
Osteoarthritis and the aging skeletal system
Osteoarthritis, the most common form of arthritis, is an aging-associated chronic disease characterized by articular cartilage degradation, dysregulated ossification (bone formation), and osteophyte (bone spur) formation. Associated with disability, morbidity, and mortality, it affects more than 350 million patients all over the world, making it one of the most common afflictions associated with aging. Dr. Chen’s group has been actively engaged in finding cures by characterizing cells in osteoarthritic patients for potential interventions.
In Liu, et al., 2020, Dr. Chen’s group not only identified a novel lateral signaling mechanism for TGF-beta in osteoarthritic patients, but implemented this finding under an existing drug that could be re-purposed for treatment for osteoarthritis. This research focused on the role of chondrocytes and mesenchymal stromal cells in the development of osteoarthritis.
The researchers first used RNA-sequencing to assess gene expression in populations of chondrocytes and mesenchymalstromal cells in order to evaluate changes during osteoarthritis progression. Typically, chondrocytes make up 90% of cartilage, whereas in osteoarthritis, mesenchymal stromal cells become more abundant. They found an unexpected result associated with pathogenesis: the stromal cells were expressing the same level of bone morphogenetic protein receptors as the chondrocytes but only a fraction of transforming growth factor beta receptors. This difference results in a lateral signaling mechanism in which transforming growth factor beta, which normally triggers cartilage regeneration in chondrocytes, activates degenerative effects in cartilage stromal cells during osteoarthritis. Taking advantage of this finding, Dr. Chen’s group suggested that, rather than targeting transforming growth factor beta, which could yield mixed outcomes, one should target its lateral signaling molecule for osteoarthritis treatment. They identified a drug candidate, which was originally developed to inhibit constitutive bone morphogenetic protein signaling during heterotopicossification. Their study went on to demonstrate that this drug could be re-purposed to inhibit joint degeneration in an animal model of osteoarthritis.
Interdisciplinary and translational applications
The findings of Liu, et al., 2020 have important implications in the fields of both osteoarthritis and aging in general, positing new mechanisms that characterize a common theme in cellular degeneration: senescence of mesenchymalstromal (stem) cells.
Senescence can refer to the cellular level or an entire organism and is a phenomenon that results in biological degeneration over time, where systems eventually break down and cease to function. Cellular senescence has become a major player in aging research, bringing with it a vast interdisciplinary approach using disease models such as osteoarthritis, neurodegeneration, endocrine disorders, and genetic factors. This study was supported by a NIH/NIAMSR61/R33 grant for innovative exploratory research projects and a NIH/NIGMS P30 grant to support the Center of Biomedical Excellence for Skeletal Health and Repair.
With the next phase of research in motion, Dr. Chen’s group plans to utilize their findings with mesenchymal stromal cells as a model to study cellular senescence. Since senescence occurs in many tissues in different ways, mesenchymal stromalcells provide an excellent representation of senescence behavior in cartilage, which can then be compared to other tissues. In collaboration with a diverse group of researchers at the Brown Center on the Biology of Aging, Dr. Qian Chen and his colleagues hope to develop a more unified understanding of senescence as a whole in human aging.