Animal Models of Osteoarthritis
TL;DR: The available species and models of OA are reviewed and their potential utility discussed and this approach represents a cornerstone for the development of new anti-OA therapeutic targets and drugs.
Abstract: The complex pathobiologic changes of human joint disease, particularly osteoarthritis (OA), normally take sev- eral decades to develop and may be influenced by a multitude of genetic and environmental factors. The need to clarify the molecular events that occur in joint tissues at the onset and during the progression of OA has necessitated the use of models, which, although imperfect, can exhibit many of the pathologic features that characterize the human disease. In vi- tro studies have proven invaluable in defining specific molecular and cellular events in degradation of joint tissues such as cartilage. However, to fully understand the complex inter-relationship between the different disease mechanisms, joint tis- sues and body systems, studying OA in animal models is necessary. Models of inflammatory arthropathies have proven predictive of clinical efficacy, with therapies that are beneficial in animals having significant benefit in treatment of rheumatoid arthritis in humans. While none of the available animal models of OA can truly be said to be predictive, as no anti-OA therapies have yet proven to be disease modifying in human trials, this approach represents a cornerstone for dis- covery of new anti-OA therapeutic targets and drugs. In this paper the available species and models of OA are reviewed and their potential utility discussed.
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TL;DR: How the latest data on potential molecular targets for PTOA prevention and modification derived from studies in genetically modified mice are translated to humans is focused on, and the potential challenges to successful implementation of clinical trials of disease-modifying drugs for OA are identified.
Abstract: Osteoarthritis (OA), the most common of all arthropathies, is a leading cause of disability and has a large (and growing) worldwide socioeconomic cost. Despite its burgeoning importance, translation of disease-modifying OA therapies from the laboratory into clinical practice has slowed. Differences between the OA models studied preclinically and the disease evaluated in human clinical trials contribute to this failure. Most animal models of OA induce disease through surgical or mechanical disruption of joint biomechanics in young individuals rather than the spontaneous development of age-associated disease. This instability-induced joint disease in animals best models the arthritis that develops in humans after an injurious event, known as post-traumatic OA (PTOA). Studies in genetically modified mice suggest that PTOA has a distinct molecular pathophysiology compared with that of spontaneous OA, which might explain the poor translation from preclinical to clinical OA therapeutic trials. This Review summarizes the latest data on potential molecular targets for PTOA prevention and modification derived from studies in genetically modified mice, and describes their validation in preclinical therapeutic trials. This article focuses on how these findings might best be translated to humans, and identifies the potential challenges to successful implementation of clinical trials of disease-modifying drugs for PTOA.
215 citations
TL;DR: This evidence-based review will compare and contrast several different animal models for knee osteoarthritis to inform the clinician about current research models, in order to facilitate the transfer of knowledge from the “bench” to the ”bedside.
Abstract: Knee osteoarthritis remains a tremendous public health concern, both in terms of health-related quality of life and financial burden of disease. Translational research is a critical step towards understanding and mitigating the long-term effects of this disease process. Animal models provide practical and clinically relevant ways to study both the natural history and response to treatment of knee osteoarthritis. Many factors including size, cost, and method of inducing osteoarthritis are important considerations for choosing an appropriate animal model. Smaller animals are useful because of their ease of use and cost, while larger animals are advantageous because of their anatomical similarity to humans. This evidence-based review will compare and contrast several different animal models for knee osteoarthritis. Our goal is to inform the clinician about current research models, in order to facilitate the transfer of knowledge from the “bench” to the “bedside.”
192 citations
TL;DR: The available data indicates that the molecular mechanisms of both joint structural damage and pain may be distinct in animal models of OA induced or initiated by different means, suggesting the need to continue using multiple OA animal models but that the subsequent interpretation of the data and its extrapolation to the human condition must be more precise.
154 citations
TL;DR: The pathophysiologic mechanisms underlying the complexity of pain in OA are presented and the challenges for new treatment strategies aiming to translate experimental findings into daily clinical practice are discussed.
153 citations
TL;DR: Tissue engineering of bone and cartilage has progressed from simple to sophisticated materials with defined porosity, surface features, and the ability to deliver biological factors as mentioned in this paper, which is called tissue engineering.
Abstract: Tissue engineering of bone and cartilage has progressed from simple to sophisticated materials with defined porosity, surface features, and the ability to deliver biological factors. To avoid elici...
145 citations
References
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TL;DR: For thirty-two areas of cartilage from nine osteo-arthritic and four "normal" femoral heads a histologic-histochemical grade was assigned as an index of severity of the osteo -arthritic process.
Abstract: For thirty-two areas of cartilage from nine osteo-arthritic and four "normal" femoral heads a histologic-histochemical grade was assigned as an index of severity of the osteo-arthritic process. The DNA and hexosamine concentrations were determined as indicators of cell density and polysaccharide con
2,168 citations
"Animal Models of Osteoarthritis" refers methods in this paper
...Even with the most commonly used histopathology grading systems based on that described by Mankin [63], the relationship between the pathological parameters scored and clinically relevant disease is not well established....
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TL;DR: The objectives of this study are to review the long-term consequences of injuries to the anterior cruciate ligament and menisci, the pathogenic mechanisms, and the causes of the considerable variability in outcome, and to strive toward a comparable level of quality of evidence in surgical treatment of knee injuries.
Abstract: The objectives of this study are to review the long-term consequences of injuries to the anterior cruciate ligament and menisci, the pathogenic mechanisms, and the causes of the considerable variability in outcome. Injuries of the anterior cruciate ligament and menisci are common in both athletes and the general population. At 10 to 20 years after the diagnosis, on average, 50% of those with a diagnosed anterior cruciate ligament or meniscus tear have osteoarthritis with associated pain and functional impairment: the young patient with an old knee. These individuals make up a substantial proportion of the overall osteoarthritis population. There is a lack of evidence to support a protective role of repair or reconstructive surgery of the anterior cruciate ligament or meniscus against osteoarthritis development. A consistent finding in a review of the literature is the often poor reporting of critical study variables, precluding data pooling or a meta-analysis. Osteoarthritis development in the injured joints is caused by intra-articular pathogenic processes initiated at the time of injury, combined with long-term changes in dynamic joint loading. Variation in outcome is reinforced by additional variables associated with the individual such as age, sex, genetics, obesity, muscle strength, activity, and reinjury. A better understanding of these variables may improve future prevention and treatment strategies. In evaluating medical treatment, we now expect large randomized clinical trials complemented by postmarketing monitoring. We should strive toward a comparable level of quality of evidence in surgical treatment of knee injuries. In instances in which a randomized clinical trial is not feasible, natural history and other observational cohort studies need to be as carefully designed and reported as the classic randomized clinical trial, to yield useful information.
2,014 citations
"Animal Models of Osteoarthritis" refers background in this paper
...In humans, meniscectomy or ACL injury will cause osteoarthritis in 50% of cases by up 10 to 20 years post-surgery [9]....
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TL;DR: The OARSI cartilage OA histopathology grading system appears consistent and simple to apply as discussed by the authors, however, further studies are required to confirm the system's utility, as well as their reproducibility and validity.
1,813 citations
TL;DR: It is demonstrated that ADAMTS5 is the primary ‘aggrecanase’ responsible for aggrecan degradation in a murine model of osteoarthritis, and rational strategies for therapeutic intervention in osteOarthritis are suggested.
Abstract: Human osteoarthritis is a progressive disease of the joints characterized by degradation of articular cartilage. Although disease initiation may be multifactorial, the cartilage destruction appears to be a result of uncontrolled proteolytic extracellular matrix destruction. A major component of the cartilage extracellular matrix is aggrecan, a proteoglycan that imparts compressive resistance to the tissue. Aggrecan is cleaved at a specific 'aggrecanase' site in human osteoarthritic cartilage; this cleavage can be performed by several members of ADAMTS family of metalloproteases. The relative contribution of individual ADAMTS proteases to cartilage destruction during osteoarthritis has not been resolved. Here we describe experiments with a genetically modified mouse in which the catalytic domain of ADAMTS5 (aggrecanase-2) was deleted. After surgically induced joint instability, there was significant reduction in the severity of cartilage destruction in the ADAMTS5 knockout mice compared with wild-type mice. This is the first report of a single gene deletion capable of abrogating the course of cartilage destruction in an animal model of osteoarthritis. These results demonstrate that ADAMTS5 is the primary 'aggrecanase' responsible for aggrecan degradation in a murine model of osteoarthritis, and suggest rational strategies for therapeutic intervention in osteoarthritis.
1,107 citations
"Animal Models of Osteoarthritis" refers background in this paper
...Meniscal destabilisation Mouse Unproven with therapeutic intervention as yet [38, 39]...
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TL;DR: Local delivery of adult mesenchymal stem cells to injured joints stimulates regeneration of meniscal tissue and retards the progressive destruction normally seen in this model of OA.
Abstract: Objective
To explore the role that implanted mesenchymal stem cells may play in tissue repair or regeneration of the injured joint, by delivery of an autologous preparation of stem cells to caprine knee joints following induction of osteoarthritis (OA).
Methods
Adult stem cells were isolated from caprine bone marrow, expanded in culture, and transduced to express green fluorescent protein. OA was induced unilaterally in the knee joint of donor animals by complete excision of the medial meniscus and resection of the anterior cruciate ligament. After 6 weeks, a single dose of 10 million autologous cells suspended in a dilute solution of sodium hyaluronan was delivered to the injured knee by direct intraarticular injection. Control animals received sodium hyaluronan alone.
Results
In cell-treated joints, there was evidence of marked regeneration of the medial meniscus, and implanted cells were detected in the newly formed tissue. Degeneration of the articular cartilage, osteophytic remodeling, and subchondral sclerosis were reduced in cell-treated joints compared with joints treated with vehicle alone without cells. There was no evidence of repair of the ligament in any of the joints.
Conclusion
Local delivery of adult mesenchymal stem cells to injured joints stimulates regeneration of meniscal tissue and retards the progressive destruction normally seen in this model of OA.
1,057 citations
"Animal Models of Osteoarthritis" refers background in this paper
...To the best of our knowledge only one study has examined the utility of stem cells to treat OA per se [70]....
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