Abstract
Osteoarthritis of the knee and spine is highly prevalent in modern society, yet a disease-modifying pharmacological treatment remains an unmet clinical need. A major challenge for drug development includes selection of appropriate preclinical models that accurately reflect clinical phenotypes of human disease. The aim of this study was to establish an ex vivo explant model of human knee and spine osteoarthritis that enables assessment of osteochondral tissue responses to inflammation and drug treatment. Equal-sized osteochondral fragments from knee and facet joints (both n = 6) were subjected to explant culture for 7 days in the presence of a toll-like receptor 4 (TLR4) agonist and an inhibitor of transforming growth factor-beta (TGF-β) receptor type I signaling. Markers of inflammation, interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), but not bone metabolism (pro-collagen-I) were significantly increased by treatment with TLR4 agonist. Targeting of TGF-β signaling resulted in a strong reduction of pro-collagen-I and significantly decreased IL-6 levels. MCP-1 secretion was increased, revealing a regulatory feedback mechanism between TGF-β and MCP-1 in joint tissues. These findings demonstrate proof-of-concept and feasibility of explant culture of human osteochondral specimens as a preclinical disease model, which might aid in definition and validation of disease-modifying drug targets.
Highlights
Osteoarthritis (OA) is a chronic disorder involving movable joints that is characterized by cell stress and extracellular matrix degradation initiated by micro- and macro-injury that activates maladaptive repair responses including pro-inflammatory pathways of innate immunity [1]
Osteochondral specimens were prepared from osteoarthritic knee tibial plateaus or facet joints
Selection of an appropriate model that accurately reflects the joint-specific pathomechanisms and clinical phenotypes observed in human disease is crucial for successful disease-modifying OA drug (DMOAD) development
Summary
Osteoarthritis (OA) is a chronic disorder involving movable joints that is characterized by cell stress and extracellular matrix degradation initiated by micro- and macro-injury that activates maladaptive repair responses including pro-inflammatory pathways of innate immunity [1]. The presence of synovial inflammation and bone marrow lesions is strongly associated with the progression of knee and facet joint osteoarthritis in humans [8,9,10]. OA severity is correlated with increased expression of a number of pro-inflammatory mediators, including interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1/CCL2) [11,12]. It has been shown in experimental and human OA that agonists of Toll-like receptor 4 (TLR4), such as lipopolysaccharide (LPS) and damage-associated molecular patterns (DAMPs) produced in the degenerated joint, play a central role in the inflammatory response in diseases joints [13,14,15,16]. A disease-modifying OA drug (DMOAD) is still lacking, and total joint replacement remains the standard symptomatic treatment for end-stage disease
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