Biology subjects

Choi, Y.-R.

Publications and source records attributed to Choi, Y.-R..

3 recordsLinked to original sources

bioRxiv2020

Adipose Tissue is a Critical Regulator of Osteoarthritis

Osteoarthritis (OA), the leading cause of pain and disability worldwide, disproportionally affects obese individuals. The mechanisms by which adipose tissue leads to the onset and progression of OA are unclear due to the complex interactions between the metabolic, biomechanical, and inflammatory factors that accompany obesity. We used a murine model of lipodystrophy (LD) to examine the direct contribution of adipose tissue to OA. Knee joints of LD mice were protected from spontaneous or post-traumatic OA, on either a chow and high fat diet, despite similar body weight and the presence of systemic inflammation. These findings indicate that adipose tissue itself plays a critical role in the pathophysiology of OA. Susceptibility to post-traumatic OA was reintroduced into LD mice using implantation of adipose tissue derived from wildtype animals or mouse embryonic fibroblasts that undergo spontaneous adipogenesis, implicating paracrine signaling from fat, rather than body weight, as a critical mediator of joint degeneration.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2019

Gene Therapy for Follistatin Mitigates Systemic Metabolic Inflammation and Post-Traumatic Osteoarthritis in High-Fat Diet-Induced Obese Mice

Obesity-associated inflammation and loss of muscle function play critical roles in the development of osteoarthritis (OA); thus, therapies that target muscle tissue may provide novel approaches to restoring metabolic and biomechanical dysfunction associated with obesity. Recent studies indicate that follistatin (FST), a protein which binds myostatin and activin, may have the potential to enhance muscle formation while neutralizing inflammation induced by these proteins. Here, we hypothesized that adeno-associated virus (AAV9) delivery of FST will enhance muscle formation and mitigate metabolic inflammation and knee OA caused by a high fat diet in mice. Obese mice receiving AAV-mediated FST delivery exhibited decreased inflammatory adipokines and cytokines systemically in the serum as well as locally in the joint synovial fluid. Regardless of diet, mice receiving FST gene therapy were protected from post-traumatic OA and bone remodeling induced by joint injury. While obesity disrupted the mitochondrial oxidative phosphorylation (OXPHOS) system in adipocytes, gene therapy for FST restored the key proteins involved in mitochondrial biogenesis, such as PPAR{gamma} coactivator 1 and AKT protein kinase 1, leading to the browning of white adipose tissue. Taken together, these findings suggest that FST gene therapy may provide a multifactorial therapeutic approach for injury-induced OA and metabolic inflammation in obesity.

physiology↗

bioRxiv2019

A Genome-engineered Bioartificial Implant for Autoregulated Anti-Cytokine Drug Delivery

Biologic drug therapies are effective treatments for autoimmune diseases such as rheumatoid arthritis (RA) but may cause significant adverse effects, as they are administered continuously at high doses that can suppress the immune system. Using CRISPR-Cas9 genome editing, we engineered stem cells containing a synthetic gene circuit expressing biologic drugs to antagonize interleukin-1 (IL-1) or tumor necrosis factor (TNF) in an autoregulated, feedback-controlled manner in response to activation of the endogenous chemokine (C-C) motif ligand 2 (Ccl2) promoter. To test this approach in vivo, cells were tissue-engineered into a stable cartilaginous construct and implanted subcutaneously in mice with inflammatory arthritis. Bioengineered anti-cytokine implants mitigated arthritis severity as measured by joint pain, structural damage, and systemic and local inflammation. The coupling of synthetic biology with tissue engineering promises a range of potential applications for treating chronic diseases using custom-designed cells that express therapeutic transgenes in response to dynamically changing biological signals.Competing Interest StatementThe authors have declared no competing interest.View Full Text

synthetic biology↗