The scoring paradigm described here has been found to be sufficiently sensitive to discriminate between treatments and to have high reproducibility. Therefore we recommend its use for evaluation of different rat OA models as well as assessment of disease-modifying effects of treatments in these models.

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Objective This review focuses on the criteria for assessing osteoarthritis (OA) in the guinea pig at the macroscopic and microscopic levels, and recommends particular assessment criteria to assist standardization in the conduct and reporting of preclinical trails in guinea pig models of OA. Methods A review was conducted of all OA studies from 1958 until the present that utilized the guinea pig. The PubMed database was originally searched August 1, 2006 using the following search terms: guinea pig and osteoarthritis. We continued to check the database periodically throughout the process of preparing this chapter and the final search was conducted January 7, 2009. Additional studies were found in a review of abstracts from the OsteoArthritis Research Society International (OARSI) conferences, Orthopaedic Research Society (ORS) conferences, and literature related to histology in other preclinical models of OA reviewed for relevant references. Studies that described or used systems for guinea pig joint scoring on a macroscopic, microscopic, or ultrastructural basis were included in the final comprehensive summary and review. General recommendations regarding methods of OA assessment in the guinea pig were derived on the basis of a comparison across studies and an inter-rater reliability assessment of the recommended scoring system. Results A histochemical-histological scoring system (based on one first introduced by H. Mankin) is recommended for semi-quantitative histological assessment of OA in the guinea pig, due to its already widespread adoption, ease of use, similarity to scoring systems used for OA in humans, its achievable high inter-rater reliability, and its demonstrated correlation with synovial fluid biomarker concentrations. Specific recommendations are also provided for histological scoring of synovitis and scoring of macroscopic lesions of OA. Conclusions As summarized herein, a wealth of tools exist to aid both in the semi-quantitative and quantitative assessment of OA in the guinea pig and provide a means of comprehensively characterizing the whole joint organ. In an ongoing effort at standardization, we recommend specific criteria for assessing the guinea pig model of OA as part of an OARSI initiative, termed herein the OARSI-HISTOgp recommendations.

IntroductionInteraction of T cells with the vascular endothelium is a critical step during T-cell extravasation from blood into tissue in immunosurveillance and inflammation. Cell adhesion molecules (CAMs) expressed on the T-cell and endothelial cell surfaces play essential roles in this intercellular interaction. The intercellular adhesion molecule 1 (ICAM-1) and ICAM-2, members of the immunoglobulin superfamily, and their ␤2-integrin ligand lymphocyte function-associated antigen 1 (LFA-1), expressed on all leukocytes, 1,2 are important for firm attachment of leukocytes to, and their subsequent migration across, the endothelium. 3 A role of endothelial ICAM-1 and ICAM-2 in LFA-1-mediated T-cell adhesion to endothelial cells as well as their transendothelial migration (TEM) has been firmly established by a number of in vitro studies. [4][5][6][7][8] In vivo expression patterns of ICAM-1 and ICAM-2 are distinct but overlapping. Overall tissue distribution of ICAM-2 is more restricted than that of ICAM-1. Both ICAMs are expressed at low levels on most leukocytes. ICAM-2 is constitutively expressed on all vascular endothelium, including high endothelial venules at much higher levels than ICAM-1. 9 ICAM-1 expression is strongly inducible by inflammatory cytokines, whereas ICAM-2 was reported to be down-regulated by inflammatory cytokines. 10 On the basis of the endothelial expression patterns of ICAM-1 and ICAM-2, it has been hypothesized that ICAM-2 mediates leukocyte traffic into noninflamed tissue, that is, lymphocyte recirculation during immunosurveillance, whereas upregulated levels of ICAM-1 may increase leukocyte extravasation at sites of inflammation. 11 Strikingly, ICAM-1-or ICAM-2-deficient mice are both viable and show relatively mild defects in their immune responses. ICAM-1-deficient mice suffer from a moderate leukocytosis while activation and migration of leukocytes to places of inflammation are reduced, resulting in impaired immune and inflammatory responses. 12 On the other hand, they are resistant to septic shock 13 and show attenuated ischemia reperfusion injury 14 owing to reduced leukocyteendothelial interaction. Interestingly, ICAM-2-deficient mice do not show any impairment in lymphocyte homing or development of leukocytes, but rather demonstrated a critical role for ICAM-2 in eosinophil trafficking. 15 Recently, an additional function for human endothelial ICAM-2 in mediating the TEM of dendritic cells (DCs) via interaction with a novel DC-specific ligand DC-specific ICAMgrabbing nonintegrin (DC-SIGN) has been demonstrated. 16 Analysis of the involvement of endothelial ICAM-1 and ICAM-2 in T-cell extravasation in vivo has been complicated even in ICAM-1 Ϫ/Ϫ or ICAM-2 Ϫ/Ϫ mice by the fact that both molecules are also involved in immune cell activation. To delineate the functional involvement of endothelial ICAM-1 versus ICAM-2 in TEM of T lymphocytes in vitro, we have established endothelial cell lines deficient for both ICAM-1 and ICAM-2 from ICAM-1 Ϫ/Ϫ ICAM-2 Ϫ/Ϫ mice. Here we show that the ...

Animal model systems represent an important adjunct and surrogate for studies of osteoarthritis (OA) in humans. They provide a means to study OA pathophysiology as well as aid in the development of therapeutic agents and biological markers for diagnosing and prognosing the disease. Thus, it is of great importance for the OA scientific community, both in academic as well as industrial research, to standardize scoring systems for evaluating the OA disease process and to make results between different studies comparable. The task of the histopathology initiative of OARSI was to achieve a consensus of scoring systems for the most important species used in OA animal model research (dog, guinea pig, horse, mouse, rabbit, rat, and sheep/goat), which are presented in the various chapters in this special volume of Osteoarthritis & Cartilage together with extra chapters on basic methodology (histochemistry, statistics, morphometry), the specific terminology and a general discussion of animal models in OA research. Standardized definitions are suggested for basic but essential terms such as "grading" and "staging" in order to promote their consistent use and thereby promote improved understanding and data interpretation across all model systems. Thus, this introductory chapter presents an overview of the guiding principles for assessment of important OA animal model systems. Use of such systems, independently or in conjunction with other systems in parallel, should facilitate comparability of results across animal model studies.

The ICE inhibitor pralnacasan reduced joint damage in two experimental models of OA and has the potential to become a disease-modifying drug for the treatment of OA.

CD44 is expressed in various isoforms on numerous cell types and tissues during embryogenesis and in the mature organism. CD44 may also be involved in tumor growth. To study the multiple roles of CD44, we abolished expression of all known isoforms of CD44 in mice by targeting exons encoding the invariant N-terminus region of the molecule. Surprisingly, mice were born in Mendelian ratio without any obvious developmental or neurological deficits. Hematological impairment was evidenced by altered tissue distribution of myeloid progenitors with increased levels of colony-forming unit–granulocyte-macrophage (CFU-GM) in bone marrow and reduced numbers of CFU-GM in spleen. Fetal liver colony-forming unit–spleen and granulocyte colony-stimulating factor mobilization assays, together with reduced CFU-GM in peripheral blood, suggested that progenitor egress from bone marrow was defective. In what was either a compensatory response to CD44 deficiency or an immunoregulatory defect, mice also developed exaggerated granuloma responses to Cryotosporidium parvum infection. Finally, tumor studies showed that SV40-transformed CD44-deficient fibroblasts were highly tumorigenic in nude mice, whereas reintroduction of CD44s expression into these fibroblasts resulted in a dramatic inhibition of tumor growth.

A 730-base pair element regulates expression of the Drosophila gap gene Krüppel (Kr) in response to the fly anterior morphogen bicoid (bcd). Two hormone receptor-like proteins, encoded by the genes knirps (kni) and tailless (tll), bind specifically to the element. In vitro, kni protein competes with the homeodomain-containing bcd protein in binding to a 16-base pair target sequence. In vivo experiments suggest that both kni and tll act as competitive repressors of bcd-mediated activation of Kr. These results suggest a mechanism by which developmental genes can be regulated in response to an activating morphogen gradient antagonized by repressors.