Impact of inflammation on the osteoarthritic niche: Implications for regenerative medicine
ABSTRACT Osteoarthritis (OA) is the most common form of arthritis worldwide and is the sixth leading cause of disability. It costs the UK economy approximately 1% of gross national product per annum. With an aging population, the cost of chronic conditions such as OA continues to rise. Historically, treatments for OA have been limited to painkillers, physiotherapy and joint injections. When these fail, patients are referred for joint replacement surgery. With the advent of tissue engineering strategies aimed at generating new bone and cartilage for repair of osteochondral defects, there has been considerable interest in exploiting these techniques to devise new treatments for OA. To date, little consideration has been given to the OA niche and attendant inflammatory milieu for any regenerative skeletal strategy. This review highlights the importance of understanding the osteoarthritic niche in order to modify existing tissue engineering and regenerative medicine strategies for the future treatment of OA.
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ABSTRACT: Osteoarthritis (OA) is a chronic degenerative disease of the articular joint that involves both bone and cartilage degenerative changes. An engineered osteochondral tissue within physiological conditions will be of significant utility in understanding the pathogenesis of OA and testing the efficacy of potential disease-modifying OA drugs (DMOADs). In this study, a dual-chamber bioreactor was fabricated and fitted into a microfluidic base. When the osteochondral construct is inserted, two chambers are formed on either side of the construct (top, chondral; bottom, osseous) that is supplied by different medium streams. These medium conduits are critical to create tissue-specific microenvironments in which chondral and osseous tissues will develop and mature. Human bone marrow stem cell (hBMSCs)-derived constructs were fabricated in situ and cultured within the bioreactor and induced to undergo spatially defined chondrogenic and osteogenic differentiation for 4 weeks in tissue-specific media. We observed tissue specific gene expression and matrix production as well as a basophilic interface suggesting of a developing tidemark. Introduction of interleukin-1β (IL-1β) to either the chondral or osseous medium stream induced strong degradative responses locally as well as in the opposing tissue type. For example, IL-1β treatment of the osseous compartment resulted in a strong catabolic response in the chondral layer as indicated by increase matrix metalloproteinase (MMP) expression and activity and tissue-specific gene expression. This induction was greater than seen with IL-1β application to the chondral component directly, indicative of active biochemical communication between the two tissue layers and supporting the osteochondral nature of OA. The microtissue culture system developed here offers novel capabilities for investigating the physiology of osteochondral tissue and pathogenic mechanisms of OA, and serving as a high-throughput platform to test potential DMOADS.Molecular Pharmaceutics 05/2014; 11(7). DOI:10.1021/mp500136b · 4.79 Impact Factor