The antifibrotic properties of relaxin-2 and its novel use for the treatment of adhesive capsulitis
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Fibrosis is an irreversible disease that affects several organs across the body. Despite the location of this disease, fibroses are presented similarly: a pathological accumulation of fibrous connective tissue. Fibroses arise as a response to repeated stimulus or injury, as dysregulated wound-healing, or idiopathically. Regardless of origin, fibroses may lead to a drastic restriction in the quality of life, precluding individuals from performing their quotidian routines or necessitating regular medical attention. Currently, the standard of care for fibrotic disease is limited to administration of corticosteroids and/or NSAIDS, or other therapies that merely address the symptoms and are palliative without confronting the underlying cause. These treatments provide inconsistent results depending on the patient, the afflicted tissue, and its severeity. This therefore calls for the development of an anti-fibrotic therapeutic that not only combats the symptoms of fibroses, but also reverses its pathology on a cellular and molecular level. This demand has led our search to the naturally-occurring pregnancy hormone relaxin-2. This insulin-like peptide hormone readies the pubic symphysis and systemic vasculature for child birth by shifting the ECM homeostasis to a less fibrotic state, augmenting cardiac output and facilitating parturition without increasing burden on the mother. Its therapeutic potential therefore lies in the its capability to stimulate the degradation of fibrous ECM proteins in addition to its systemic safety and tolerability. Previous studies using relaxin-2 have evaluated its anti-fibrotic potential in the liver, heart, and lungs and have thus incentivized us to test its efficacy in the synovial joint space. Herein, this work encompasses the use of relaxin-2 is to ameliorate arthrofibrosis with multiple, intra-articular (IA) injections in the synovial joint space in a murine model of adhesive capsulitis. The pharmacokinetic profile of relaxin-2 from an IA bolus is determined in the synovium, serum, liver, heart, kidneys, and spleen. Sustained release formulations are created and evaluated for their in vivo efficacy. Lastly, preliminary stages of the recombinant expression and purification of a site-specific-modifiable relaxin-2 analog are discussed as well as its in vitro evaluation for its use as an anti-scarring agent.
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