Extracellular matrix stiffening is a quintessential feature of cartilage aging, a leading cause of knee osteoarthritis. Yet, the downstream molecular and cellular consequences of age-related biophysical alterations are poorly understood. Here, we show that epigenetic regulation of α-Klotho represents a novel mechanosensitive mechanism by which the aged extracellular matrix influences chondrocyte physiology. Using mass spectrometry proteomics followed by a series of genetic and pharmacological manipulations, we discovered that increased matrix stiffness drove Klotho promoter methylation, downregulated Klotho gene expression, and accelerated chondrocyte senescence in vitro. In contrast, exposing aged chondrocytes to a soft matrix restored a more youthful phenotype in vitro and enhanced cartilage integrity in vivo. Our findings demonstrate that age-related alterations in extracellular matrix biophysical properties initiate pathogenic mechanotransductive signaling that promotes Klotho promoter methylation and compromises cellular health. These findings are likely to have broad implications even beyond cartilage for the field of aging research.
Microphysiological
systems, including organoids, 3-D printed tissue
constructs, and organ-on-a-chip systems (organ chips), are physiologically
relevant in vitro models and have experienced explosive
growth in the past decades. Different from conventional, tissue culture,
plastic-based in vitro models or animal models, microphysiological
systems recapitulate key microenvironmental characteristics of human
organs and mimic their primary functions. The advent of microphysiological
systems is attributed to evolving biomaterials, micro/nanotechnologies,
and stem cell biology, which enable precise control over the matrix
properties and the interactions between cells, tissues, and organs
in physiological conditions. As such, microphysiological systems have
been developed to model a broad spectrum of organs from microvasculature
and eyes to lungs and many others to understand human organ development
and disease pathology and facilitate drug discovery. Multiorgans-on-a-chip
systems have also been developed by integrating multiple associated
organ chips in a single platform, which allow study and employment
of the organ function from a systematic approach. Here we first discuss
the design principles of microphysiological systems with a focus on
the anatomy and physiology of organs and, then, review the commonly
used fabrication techniques and biomaterials for microphysiological
systems. Subsequently, we discuss recent developments in microphysiological
systems and provide our perspectives on advancing microphysiological
systems for preclinical investigation and drug discovery of human
disease.
(125)IUdR treatment proved to be feasible without acute neurological toxicity and seemed to have produced a biological response. This attempt provides the basis for designing prospective clinical trials.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.