Award: Arthritis and Related Autoimmune Disease Research Grant
Biography: I am a new Assistant Professor at Washington University in St Louis, focused on understanding mechanisms of cell-cell crosstalk in osteoarthritis. My training in molecular cell biology and immunology has encompassed many domains, including systemic inflammation, obesity and metabolic disease, liver disease, bone fracture healing, and osteoarthritis. During my graduate and postdoctoral training, I made significant contributions to our understanding of thermogenic fat activation and the cellular protagonists involved, and also defined a hierarchy of stromal cells and lineages in joint synovium that advances our understanding of how the intra-articular cellular landscape dramatically changes after injury. Critically, this latter work provides a roadmap for studying stromal lineages that exist in steady-state synovium and joint fat, as well as the pathological emergent lineages that arise following joint injury. Now, my independent work will integrate different aspects of my training to better understand crosstalk mechanisms in healthy joints and how these communications break down following joint trauma, leading to osteoarthritis. Ultimately, I hope to uncover new, innovative targets for treatment that have not been historically considered in the field, and importantly, help to develop more effective modes of delivery and administration to improve patient outcomes.
Research Summary: Osteoarthritis (OA) is a painful and debilitating joint disease afflicting over half a billion people worldwide – yet, no disease-modifying treatments exist. Post-traumatic osteoarthritis (PTOA) is a type of OA that arises after joint injury, and we now appreciate that PTOA is not simply a disease of cartilage ‘wear-and-tear’ – all joint tissues are implicated. Recent attention has shifted to fat, or adipose tissue, for its potential pathological or pro-regenerative functions in PTOA. Fat is present in healthy joints, but in PTOA, can be replaced by fibrotic scarring and pain-sensing nerves which contribute to joint pain and stiffness. Thus, there is strong impetus to understand adipose tissue in healthy and PTOA joints.
Adipocytes, or fat cells, are primarily involved in energy storage. However, they also have the unique ability to generate heat by burning stored energy, in order to regulate body temperature (eg. in cold). This phenomenon is called ‘adaptive thermogenesis’, and it can profoundly remodel adipose tissue in ways that may be beneficial for mitigating PTOA; however, adipose thermogenesis has never been studied in joint disease. This proposal will investigate how thermogenic activation of joint fat alters PTOA progression. We will map the emergence of thermogenic fat cells in the joint during cold exposure, and we aim to uncover mechanisms by which this process occurs. This work has highly transformative potential for the field and for translation into the clinic. Ultimately, our objective is to harness the pathways activated via thermogenesis to successfully treat PTOA.
https://orthopaedicresearch.wustl.edu/labs/alexander-knights/
