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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Osteoarthritis Cartilage. Author manuscript; available in PMC Jan 3, 2012.
Published in final edited form as:
PMCID: PMC3249463
NIHMSID: NIHMS108284

Transglutaminase 2 is a Marker of Chondrocyte Hypertrophy and Osteoarthritis Severity in the Hartley Guinea Pig Model of Knee OA

Abstract

Objective

The transglutaminase (TG) isoenzyme TG2, which catalyzes protein cross-linking via transamidation, influences healing phenotype in multiple forms of tissue injury. Moreover, TG2 knockout suppresses cartilage destruction but promotes osteophyte formation in instability-induced mouse knee OA. TG2 is marker of growth plate chondrocyte hypertrophy. Moreover, TG2 secreted by chondrocytes acts in part by promoting chondrocyte maturation to hypertrophy, a differentiation state linked with MMP-13 expression and disease progression in OA. Moreover, glucosamine, which is currently under investigation as an OA therapy, binds and inhibits TG2. Here, we examined TG2 as a potential marker of cartilage hypertrophy in the spontaneous guinea pig model of OA.

Methods

Synovial fluid ELISA and cartilage Immunohistochemistry and quantitative RT-PCR, were used to examine TG2 expression and TG transamidation-catalyzed isopeptide bonds.

Results

TG isopeptide bonds and TG2 were most abundant in articular cartilage in early knee OA. TG2 expression was robust at sites of early but not established osteophytes. Synovial fluid TG2 correlated with knee OA total histological score (r=0.47, p=0.01), as did medial tibial plateau cartilage TG2 mRNA (r=1.0, p=0.003). At 12 months of age, medial tibial plateau cartilage TG2 mRNA expression rose markedly in association with elevated type X collagen, as well as ADAMTS-5, and MMP-13 expression, changes not shared in age-matched Strain 13 guinea pigs that are less susceptible to knee OA.

Conclusion

Hartley guinea pig knee TG2 expression associates with enhanced articular chondrocyte hypertrophy and is a biomarker of OA severity.

Keywords: Osteoarthritis Biomarkers, Chondrocyte Hypertrophy, MMP-13, ADAMTS-5, Strain 13

INTRODUCTION

Alterations in extracellular matrix and matrix-cell communication regulate the differentiation, viability, and tissue remodeling functions of articular cartilage chondrocytes, thereby modulating OA clinical phenotype and outcome (1,2). Transglutaminase 2 (TG2) (913) belongs to a family of enzymes that catalyze calcium-dependent transamidation, generating covalent crosslinks of available substrate glutamine residues with primary amino groups (EC 2.3.2.13) (14). Transamidation modifies proteins including fibronectin and collagens that have available substrate amino acids, and TGs thereby alter protein-protein interactions (14). TGs are classic wound repair enzymes implicated as essential for tissue remodeling reactions to injury such as pulmonary and dermal fibrosis, cardiac hypertrophy, and reshaping of injured arteries (14). Aging alone, IL-1β, TNFα, as well as nitric oxide, peroxynitrite donors, and certain chemokines induce TG activity in chondrocytes (9,1113). Articular chondrocytes express not only TG2, but also the more tissue-restricted TG isoenzyme, FXIIIA (913).

Increased FXIIIA and TG2 expression and release are associated with physiologic maturation to hypertrophy of growth plate chondrocytes (15,16). The growth plate chondrocyte hypertrophy functional program remodels the extracellular matrix, partly through a shift in cartilage-specific collagens from type II to type X collagen as well as by enhanced MMP-13 and ADAMTS-5 and diminished aggrecan expression (15,16). Articular cartilage chondrocytes are physiologically in a maturationally arrested state, but hypertrophic differentiation develops within the population of human OA chondrocytes in situ (17). Chondrocyte hypertrophy also develops within the first few weeks in experimental joint instability-induced mouse knee OA and promotes disease progression, as demonstrated in studies of runx2-deficient mice (18).

TG2 and FXIIIA expression, as well as total TG catalytic activity and TG-catalyzed isopeptide bond formation, are substantially increased in human knee OA cartilage chondrocytes (9,10,19). TG2 is essential to accelerate cultured chondrocyte maturation to hypertrophy in response to signals provided by retinoic acid, CXCL1, the calgranulin S100A11, and FXIIIA (12,2022). Externalization of TG2 is essential to this activity (13). Moreover, exogenous nanomolar TG2 is sufficient to directly induce hypertrophic differentiation in chondrocytes in articular cartilage organ culture (13). Yet, it is not known how TG2 is secreted, since it lacks a signal peptide (14).

Secreted biomarkers detectable in the joint fluid, serum, or urine, that reflect initial, pre-radiographic stages of OA have the potential to help stratify risk of progression, monitor disease course, and improve efficacy of OA therapeutics (2326). TG2 release is critical for determining the repair phenotype of multiple forms of tissue injury (14,27,28). Furthermore, TG2 knockout was recently observed to suppress cartilage destruction but to promote osteophyte formation in a model of surgical instability-induced severe mouse knee OA (29). In addition, glucosamine, currently being investigated as an OA therapeutic (30), binds TG2 and (at low millimolar concentrations) inhibits TG2, acting more effectively on cell-associated rather than free TG2, and modulating TG2 confirmation more than amine transfer (31). Therefore, this study tested the hypothesis that TG2 is a biomarker of cartilage hypertrophy and OA severity. We employed the well-characterized Hartley guinea pig model of spontaneously occurring OA, which has several similarities to the development of OA in humans (3239). We observe TG2 to be a biomarker of OA severity in Hartley guinea pig knees.

MATERIALS AND METHODS

Sample Collection

All aspects of this study were humane and approved at the Institutional Animal Care and Use Committee level. Male Hartley guinea pigs were obtained from Charles River Laboratories at 2 months age and sacrificed at 2, 4, 7, 10, 12 (n=6 each) and 18 months (n=10). Animals were housed in solid bottom cages and fed water ad libitum and standard guinea pig chow (Purina Lab Diet 5025) containing Vitamin C (1 mg/g) and Vitamin D3 (3.4 IU/g)(36). All animals were acclimated to housing conditions for at least 1 week prior to sample collection. Synovial fluid was collected from both knees, pooled and stored at −80° C until analyzed as described (35). One knee joint was prepared for histological grading and cartilage was harvested separately from the medial and lateral compartments of the other knee joint, pooling cartilage from each time point to provide a quantity of tissue sufficient for RNA isolation and subsequent production of cDNA.

Histological Analyses

Knee joints were prepared for histological analyses as described (36). Paraffinized coronal sections (5 microns) of the central region of the joint were stained with toluidine blue and grading of sections of each knee was performed independently by 2 blinded observers (JLH, VBK) using a previously described, modified Mankin grading scheme (35). Histological evidence of chondropathy was assessed by grading of articular cartilage structure (irregularities such as fibrillation, the presence of clefts, and loss of cartilage [0–8]), and proteoglycan loss (as determined by loss of toluidine blue staining [0–6]). The sum of articular cartilage structure and proteoglycan loss was tabulated for the tibial and femoral condyles for the medial compartment, the lateral compartment, and the whole joint (medial and lateral compartments). The possible total score for each compartment ranged from 0 (normal) to 14 (severe structural damage and complete loss of toluidine blue staining), hence possible whole joint scores ranged from 0–56.

Immunohistochemistry

Immunohistochemical analyses utilized monoclonal antibodies (mAbs) specific for guinea pig TG2 (#MS-224-P, Lab Vision, Fremont, CA), FXIIIA (#MS 1237-P1. Lab Vision, Fremont, CA), N-epsilon gamma glutamyl lysine (#ab424, Abcam Inc, Cambridge, MA), the isopeptide bond formed specifically by TG activity, MMP-13 (mAb 3C5, kindly provided by Dr. Peter Mitchell), and Type X collagen (#LSL-LB-0092, Cosmo-Bio, Tokyo). Sections were deparaffinized and hydrated using xylene and a graded alcohol series followed by incubation with 0.3% hydrogen peroxide to quench any endogenous peroxidase activity. Sections used only for staining with TG2 mAb required use of the citrate buffer epitope retrieval method to break the protein cross-links formed by formalin fixation of the tissue. Sections were covered with 10 mM citrate buffer, pH 6.0, heated in a microwave for 5 seconds, and the buffer was replaced and sections were heated for an additional 5 seconds, allowed to cool, and then rinsed in PBS. Immunohistochemical staining was done according to manufacturer instructions using the Vectastain ABC kit (#PK-4002, Vector Laboratories, Burlingame, CA). The sections were incubated with antibody to TG2 or FXIIIA (2 µg/ml), the N-epsilon gamma glutamyl lysine mAb (20 µg/ml), MMP13 mAb (diluted 1:50), Type X Collagen (diluted 1:100), or normal horse serum as negative control.

Biomarker Analyses by ELISA

Direct ELISA, using biotin-labeled TG2-specific antibody CUB7402 or FXIIIA specific antibody (Neomarkers, Freemont, CA) (21), was used to quantify synovial fluid levels of TG2 and FXIIIA protein (21) in studies of samples previously analyzed for COMP by ELISA (38). The fluids were concentrated with 100% TCA, and the pellet was then washed, solubilized and dissolved in buffer, and the protein was bound to a Nunc ELISA plate overnight at 4°C. Plates were then blocked with 3% BSA in 150 mM NaCl, 10 mM Tris, Ph 8.0, 0.05% Tween-20, followed by incubation with biotin-labeled antibody. Strepavidin-alkaline phosphatase (AP) was added and the amount of TG2 or FXIIIA quantified at OD 405 nm after addition of AP substrate.

Real-time quantitative PCR

Cartilage was harvested separately from the medial and lateral compartments of the knee joint, pooling cartilage from each time point to provide a quantity of tissue sufficient for RNA isolation and subsequent production of cDNA utilized for the quantification of gene expression by real-time qPCR. Following amplification, a monocolor relative quantification of the target gene and reference (18S) analysis determined the normalized target gene: 18S mRNA copy ratios by the manufacturer's LightCycler Software (Version 4.0). The primers employed where designed using LightCycler Probe software, version 2.0 (Roche, Diagnostics, Indianapolis, IN).

Statistical Analyses

Data were examined for correlations with total joint histological score using GraphPad Prism 4.0. Pearson correlation was used to evaluate the relationship of synovial fluid levels of TG2 and FXIIIA to total histological score and the non-parametric Spearman correlation was used to calculate the correlation of mRNA values to total histological score. Multiple regression modeling was performed in JMP (SAS, Cary, NC) and used to evaluate the association of these biomarkers with histological OA severity, controlling for age, weight, and serum COMP, with p-value ≤ 0.05 considered significant. Statistical analyses of quantitative mRNA expression employed the Student's t test for paired samples (Fig. 4) and log transformation of the data followed by a two-tailed unpaired Student's t-test comparing Strain 13 to Hartley guinea pigs (Fig. 5).

Figure 4
Changes with increasing age in steady-state MMP-13, ADAMTS-5, type II:type X collagen, and TG2 mRNA levels in Hartley guinea pig cartilage of the lateral and medial tibial plateau
Figure 5
Comparison of TG2, type X collagen, and MMP-13, and ADAMTS-5 mRNA expression in Hartley and Strain 13 guinea pig medial tibial plateau OA cartilages, reveal higher levels of all but ADAMTS-5 in Hartley

RESULTS

Localization of TG2, FXIIIA, and N-epsilon gamma glutamyl lysine cross-links in Hartley guinea pig knee cartilage

The development of spontaneous knee OA in the Hartley guinea pig knee begins as early as 3 months of age, when loss of proteoglycans typically becomes apparent (39). We observed the characteristic progression of OA histological changes from 4–12 months of age in the Hartley guinea pig medial tibial plateau articular cartilage ranging from a score of 1.5 at 4 months and increasing to a score of 11.2 at 12 months of age. The time points of 4 and 7 months of age were selected to determine biomarkers indicative of early events occurring in the development of OA. Changes that developed in the medial tibial plateau between 4–7 months included fibrillation of the superficial zone, and proteoglycan loss in the superficial and middle zones (Fig. 1).

Figure 1
TG isoenzymes, TG isopeptide bonds, Factor XIIIA, and MMP-13 in the medial tibial plateau of the Hartley guinea pig knee at 4, 7 and 12 months of age

In coronal sections of guinea pig knees, TG2 was detected in the superficial and middle zones of the cartilage by 4 months of age (Figure 1). By 7 months of age, TG2 was prominent in both the cartilage, especially superficially (Figure 1) and in developing osteophytes (Figure 2) but less in hypocellular regions of cartilage. The immunostaining in osteophytes mirrored that of the other stereotypic chondrocyte hypertrophy markers (12), MMP-13 in cartilage (Fig. 1), and type X collagen in osteophytes (Fig. 2). Developing osteophytes at 7 months also demonstrated robust formation of TG-catalyzed isopeptide bonds and expression of FXIIIA (Fig. 2). Synovial TG2 immunostaining was prominent at 7 months and faint but present at 4 and 12 months (not shown). TG-catalyzed N-epsilon gamma glutamyl lysine cross-links (isopeptide bonds) and expression of the TG isoenzyme FXIIIA increased from 4 to 7 months, particularly in the middle and superficial zones (Fig. 1). Immmunostaining for TG2, FXIIIA, and TG-catalyzed isopeptide bonds was less intense in established osteophytes at 12 months of age compared with developing osteophytes at 7 months, in association with the evolution to osteophyte calcification at the joint margins.

Figure 2
TG isoenzymes and TG isopeptide bonds in osteophytes of the Hartley guinea pig knee OA at 4, 7, and 12 months of age

Synovial fluid TG2 is a biomarker of OA severity in Hartley guinea pig knees

Concentrations of TG2 protein in Hartley guinea pig knee synovial fluid, measured between 7 and 18 months of age, correlated significantly with total histological score from 7–18 months of age (r=0.47, p=0.014) (Fig. 3A). TG2 concentrations also correlated with synovial fluid COMP (r=0.39, p=0.05). The association of TG2 with histological outcome remained significant after adjusting for the effects of age, weight, and COMP. As a comparator for TG isoenzymes, we assessed synovial fluid levels of FXIIIA. There was no association of the FXIIIA synovial fluid levels from 7 to 18 months of age with total histological score (Fig. 3B: r=0.16, p=0.41).

Figure 3
Correlation of synovial fluid TG2, but not the TG isoenzyme FXIIIA, to total histological score of OA in Hartley guinea pigs

Articular chondrocyte TG2 mRNA is associated with chondrocyte hypertrophy and coincident with histological OA in Hartley guinea pig knees

From 2 to 18 months of age, the medial cartilage TG2 mRNA expression was significantly correlated with the mean total histological score, as well as with medial compartment OA score (r=1.0, p=0.003). In contrast, there was no significant correlation between FXIIIA mRNA expression and total histological score from 2 to 18 months of age (r=0.71, p=0.136). Steady-state mRNA levels of MMP-13, ADAMTS-5, type X:type II collagen ratio increased in the medial compartment of the Hartley guinea pigs at 12 months of age (Fig. 4). Under these conditions, steady-state mRNA expression of TG2 in guinea pig cartilage was detectable at low levels in the lateral compartment and increased progressively from 4 to 18 months of age in the tibial plateau medial compartment (Fig. 4).

Strain 13 guinea pigs have a markedly decreased susceptibility to spontaneous knee OA in comparison to the Hartley strain (35). We observed higher levels of TG2 mRNA in Hartley than Strain 13 guinea pig knees, and particularly so in the medial compartment (p=0.0017) (Fig. 5). Though levels of ADAMTS-5 mRNA were also elevated in the medial compartment at 12 months of age, this expression pattern was not specific to the Hartley strain guinea pigs (Fig. 5D). In contrast, at 2 months of age, prior to evidence of histological OA, compared to the Strain 13 guinea pig, the type X:type II collagen mRNA ratio was significantly greater in the Hartley guinea pigs in both the medial and lateral compartments (p<0.0001) (Fig. 5C). In addition, mRNA levels of MMP-13 and the type X:type II collagen mRNA ratio were significantly higher in the medial tibial plateau of the Hartley compared to the Strain 13 guinea pigs at 12 months of age (Fig. 5B, C, p<0.0001).

DISCUSSION

Hartley guinea pig spontaneous knee OA, like human OA, is mediated by multiple factors, including obesity, altered biomechanicals, aging, and chondrocyte nitric oxide generation and mitochondrial dysfunction (3239). Articular cartilages in OA in both species express MMPs-1,3,13 and aggrecanases (34,40), and biomarkers reflective of OA severity (e.g., keratan sulfate (KS) (35), cartilage oligomeric matrix protein (COMP) (36), and markers of type II collagen degradation and synthesis (38)). Several biomarkers evaluated in guinea pig synovial fluid correlate with severity of joint disease, whereas serum markers todate have not reflected localized disease (38). Here, guinea pig OA cartilage and synovial fluid were a platform for examining TG2 as a biomarker during disease evolution.

Both TG2 synovial fluid protein and knee cartilage mRNA levels correlated with histological OA grade in Hartley guinea pig knees. These findings are in line with the reported direct role of TG2 in promoting cartilage destruction in OA (29), putatively by promoting altered chondrocyte differentiation (12,13) and by modifying extracellular matrix (14,22). Synovitis may also contribute to synovial fluid TG2 levels and contribute to the synovial fluid TG2 pool in a disease severity-specific manner.

TG2 is the major catalytically active TG in the extracellular matrix in human OA cartilage (10), but both TG2 and FXIIIA undergo physiologic up-regulation in growth plate hypertrophic chondrocytes and pathologic up-regulation in OA cartilage (9,15,16). Here, cartilage and synovial fluid FXIIIA mRNA did not correlate with OA severity. Possibly contributing to these findings, TG2 and FXIIIA have distinct substrate motifs (41), and susceptibility to and molecular mechanisms of proteolysis (14,42). There is likely different stability of TG-catalyzed isopeptide bonds in OA tissue than of the parent proteins producing these crosslinks (14) (and possibly of TG isoenzyme mRNA levels). Increased TG-catalyzed isopeptide bonds in articular cartilage in early evolution of OA also may reflect release of constitutively expressed TG2 and FXIIIA, whose activation from latency is promoted by extracellular exposure to increased free calcium (14). The relatively late increases in TG2 mRNA expression in chondrocytes, in the setting of both ongoing cartilage repair and decreased cellularity, are consistent with accelerated chondrocyte maturation to hypertrophy, validated by type X collagen expression, now well described as contributing to advancing OA (18,43).

Hartley and Strain 13 guinea pigs similarly demonstrated increased ADAMTS-5 mRNA (44) expression at 12 months of age, but. Strain 13 guinea pig knee cartilage showed lower expression of genes associated with the hypertrophic cartilage phenotype, even at 2 months of age, consistent with less severe OA in this model. One speculates that predisposition of Hartley guinea pig chondrocytes to hypertrophic differentiation could promote increased susceptibility to OA relative to Strain 13.

Limitations of this study included uncertainty as to relative contributions of synovium, infiltrating leukocytes, and cartilage to synovial fluid TG2. In view of limiting amounts of tissue, we studied few time points, and could thereby have missed initial up-regulation of TG2, FXIIIA, and type X collagen mRNA. Kamekura et al have shown that increased type X collagen expression develops prior to OA progression in response to surgically-induced mouse knee joint instability (18). Here, Type X collagen expression was detected within articular cartilages of Hartley guinea pigs by 4 months of age, possibly indicative of early OA or reflective of basal expression of type X collagen, which is a normal finding in mouse articular cartilage (45).

We conclude that TG2 expressed by chondrocytes in situ and released into the synovial fluid, is a biomarker of OA severity. TG2 mRNA expression in this model system also coincides with manifestations of the articular chondrocyte hypertrophic differentiation response associated with type X collagen and MMP-13 expression. Because TG2 drives both hypertrophy of cultured chondrocytes (12) and progression of articular cartilage destruction in mouse knee OA (21), TG2 appears to be a prime example of a direct modulator of chondrocyte differentiation that affects the phenotype of tissue repair in OA.

Acknowledgements

We acknowledge Ms. Susan Reeves for expertise in preparing histological figures.

Supported by grants from the VA Research Service and NIH (AR049056, AG15108, AR050245, AG07998)

Footnotes

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