Abstract
Osteoarthritis (OA) is a degenerative joint disease for which there are no disease modifying therapies. Thus, strategies that offer chondroprotective or regenerative capability represent a critical unmet need. Recently, oral consumption of a hydrolyzed type 1 collagen (hCol1) preparation has been reported to reduce pain in human OA and support a positive influence on chondrocyte function. To evaluate the tissue and cellular basis for these effects, we examined the impact of orally administered hCol1 in a model of posttraumatic OA (PTOA). In addition to standard chow, male C57BL/6J mice were provided a daily oral dietary supplement of hCol1 and a meniscal-ligamentous injury was induced on the right knee. At various time points post-injury, hydroxyproline (hProline) assays were performed on blood samples to confirm hCol1 delivery, and joints were harvested for tissue and molecular analyses were performed, including histomorphometry, OARSI and synovial scoring, immunohistochemistry and mRNA expression studies. Confirming ingestion of the supplements, serum hProline levels were elevated in experimental mice administered hCol1. In the hCol1 supplemented mice, chondroprotective effects were observed in injured knee joints, with dose-dependent increases in cartilage area, chondrocyte number and proteoglycan matrix at 3 and 12 weeks post-injury. Preservation of cartilage and increased chondrocyte numbers correlated with reductions in MMP13 protein levels and apoptosis, respectively. Supplemented mice also displayed reduced synovial hyperplasia that paralleled a reduction in Tnf mRNA, suggesting an anti-inflammatory effect. These findings establish that in the context of murine knee PTOA, daily oral consumption of hCol1 is chondroprotective, anti-apoptotic in articular chondrocytes, and anti-inflammatory. While the underlying mechanism driving these effects is yet to be determined, these findings provide the first tissue and cellular level information explaining the already published evidence of symptom relief supported by hCol1 in human knee OA. These results suggest that oral consumption of hCol1 is disease modifying in the context of PTOA.
Highlights
Osteoarthritis (OA) is one of the most prevalent diseases in the world, with recent estimates projecting that >250 million people are afflicted globally [1]
Over the past two decades, more than a dozen human clinical trials have been performed to test candidate disease modifying OA drugs (DMOADs), none of which have emerged to be accepted as a bona fide therapeutic agent [10, 11]
It should be noted that while the synovial expression of other genes, including Il1β, Prg4 and Mmp13, was increased following injury, at 12 weeks post-meniscal-ligamentous injury (MLI), hCol1 supplementation did not have a significant impact on expression level. These findings suggest that dietary supplementation with hCol1 reduces synovial hyperplasia and mitigates synovial Tnf expression in both early and mid-stage posttraumatic OA (PTOA)
Summary
Osteoarthritis (OA) is one of the most prevalent diseases in the world, with recent estimates projecting that >250 million people are afflicted globally [1]. Global medical costs for lower extremity OA exceed $350 billion/year, with the reduced quality of life and physical function of OA patients exerting an additional hidden economic impact that surpasses $50 billion/year [4] Despite these statistics, there are no disease modifying therapies available, with management of OA patients consisting only of symptom palliation [5, 6] via nonsteroidal anti-inflammatory drugs, intraarticular injection of corticosteroids or hyaluronic acid, narcotic-based analgesia including opioids, and joint arthroplasty. Over the past two decades, more than a dozen human clinical trials have been performed to test candidate disease modifying OA drugs (DMOADs), none of which have emerged to be accepted as a bona fide therapeutic agent [10, 11] This list includes orally administered nutraceutical agents comprised of cartilage matrix components that are widely marketed as joint protective. In the case of chondroitin sulfate and glucosamine, the two most widely available and top selling formulations, mixed clinical trial results leave open the question of their efficacy [12]
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