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Arthritis Biology, Department of Arthritis and Bone Metabolism, Novartis Pharma AG, Basle, Switzerland;
Arcus Sportklinik, Pforzheim, Germany; and
Novartis Institute for Biomedical Research, Functional Genomics, Novartis Pharmaceuticals Corporation, Summit, NJ 07901
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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induced
SAA3 transcription in primary rabbit chondrocytes in
vitro. Furthermore, rSAA3 protein induced transcription of matrix
metalloproteinases in rabbit chondrocytes in vitro. In the human
experimental system, IL-1 induced transcription of acute-phase SAA
(A-SSA; encoded by SAA1/SAA2) in primary chondrocytes.
Similar to the rabbit system, recombinant human A-SAA protein was able
to induce matrix metalloproteinases’ transcription in chondrocytes.
Further, immunohistochemistry demonstrated that A-SAA was highly
expressed in human RA synovium. A new finding of our study is that
A-SSA expression was also detected in cartilage in osteoarthritis. Our
data, together with previous findings of SAA expression in RA synovium,
suggest that A-SAA may play a role in cartilage destruction in
arthritis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Analyzing the gene expression profile in diseased relative to
normal tissue will contribute to a better understanding of the
molecular mechanism underlying RA. In this study, we describe the
results of gene expression profiling in the rabbit model of Ag-induced
arthritis (AIA), which in many aspects, such as histopathology and
phenotype of tissue degradation, resembles the human disease. Total RNA
from control and diseased synovium was isolated and used to generate
cDNAs. Using hybridization of complex amplified cDNA probes
to high-density filter arrays and cDNA representational difference
analysis (RDA), we were able to identify genes that were differentially
expressed in the diseased synovium. The fact that the majority of the
differentially expressed genes that have a significant match to a known
gene in GenBank had previously been implicated in RA or inflammatory
responses in general supports the validity of our experimental approach
using the rabbit AIA model. Differentially expressed genes included
metalloproteinases such as collagenase-1, collagenase-3, stromelysin,
cysteine proteases such as cathepsin D, cell surface molecules
like CD44, as well as proteinases that are involved in the activation
of proinflammatory cytokines such as IL-1 converting enzyme (F.F.,
P.W., C.T., R.V., and G.B., unpublished results). However, as the major
difference product in rabbit AIA we identified SAA3. Thus we
concentrated our further studies on a potential role of SAA in
RA.
In this study, we describe a functional analysis of SAA3 and provide evidence that rabbit SAA3 and as well as the human A-SAA induce transcription of MMPs in chondrocytes in vitro suggesting that they probably also play an important role in vivo for the pathogenesis of arthritis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animal model of AIA in rabbit
Animal experiments were performed in accordance with the animal experimentation guidelines and laws of the Swiss Federal and Cantonal Authorities as described in the Basel-Stadt Experimental License No. 1438. Female dwarf Russian rabbits were sensitized intradermally to methylated BSA (mBSA) homogenized 1:1 with CFA on days -28 and -14 (0.5 ml containing 4 mg/ml mBSA). On day 0, rabbits were anesthetized for the intraarticular injections. The right knee received 0.5 ml of 2 mg/ml mBSA in 5% glucose, while the left knee received 0.5 ml of 5% glucose alone. Rabbits (n = 3) were killed on day 7. The synovium of the Ag-challenged and vehicle-injected joint was prepared and total RNA was isolated. Experiments were repeated twice.
Solid-phase cDNA library construction
Total RNA from control and disease synovium (day 7) was isolated (RNeasy; Qiagen, Hilden, Germany) and reverse transcribed on paramagnetic oligo(dT)25 Dynabeads (Dynal, Oslo, Norway). Due to low amounts of total RNA, the resulting cDNA was amplified by PCR as previously described (16).
Hybridization of high-density filter arrays with complex, amplified cDNA probes
The solid-phase library derived from control and diseased synovium was used to generate complex amplified cDNA probes. A cDNA-library from diseased synovium (day 7) was arrayed on high-density filters using a Q-bot picking and spotting robot device (Genetix, New Milton, U.K.) as previously described (17). On each filter, 9216 clones were arrayed in duplicate. Complex amplified cDNA probes were labeled with P-33 using the rediprime kit (Amersham Pharmacia Biotech, Freiburg, Germany) according to the manufacturer’s instructions. Identical high-density filter arrays were hybridized with complex, amplified cDNA probes (2 x 106 cpm/ml) derived from control and disease tissue, respectively. cDNA clones representing differentially expressed genes were sequenced and compared with sequences in GenBank using the Basic Local Alignment Search Tool (BLAST) (Genetics Computer Group, Madison, WI) program.
Representational difference analysis (RDA)
RDA was performed essentially as described (18) omitting the third subtractive hybridization round. The second difference product was subcloned into the BamHI site of pBluescript II SK+ (Stratagene, La Jolla, CA). Plasmid DNA was prepared and analyzed by sequencing. Resulting sequences were compared with GenBank database using the BLAST program.
In situ hybridization
Nondecalcified rabbit knee joints (day 7) were fixed in 4% paraformaldehyde. Following an ascending ethanol series, the joints were embedded in methylmethacrylate (Leica HistoDur, Nussloch, Germany) and sections were cut as previously described (19). For in situ hybridization, the plastic was removed by immersion in 2-methoxyethyl acetate. Subsequent steps were performed as described (20) with minor modifications. The antisense and sense riboprobes were labeled with P-33 UTP and SDS was added to a final concentration of 0.5% to the hybridization buffer to facilitate the penetration of the labeled probe into the tissue. After hybridization, slides were dipped in NTB-3 emulsion, dried at room temperature and exposed for 10 days. Exposed slides were developed with D-19 developer and analyzed by microscopy. Experiments were repeated using sections from three different animals.
Northern blot analyses
If not mentioned otherwise, 10 µg total RNA were denatured, separated on a 1% agarose gel, and transferred onto Hybond N+ membrane (Amersham Pharmacia Biotech). The filters were hybridized with random primed radioactively labeled cDNA specific for rabbit MMP-13 (21), rabbit SAA3 (22), human MMP-1 (23), and human SAA1 (24) as described (25).
Expression and purification of rSAA-protein
A cDNA fragment representing the mature SAA3 protein with
an artificial start codon followed by six amino-terminal histidine
residues was amplified by PCR using the following primer combination:
5'-CAGGTCAACTCATATGCATCACCATCACCATCACCGTGAATGGTTAACATTCC-3' and
5'-CAGGTCAACTCATATGCGTGAATGGTTAACATTCC-3'. The PCR product was
digested with NdeI/XhoI and cloned into the
bacterial expression vector pET-17b. The correct sequence of the
expression construct was confirmed by DNA sequence analysis. Expression
of the recombinant protein was induced in Escherichia coli
(BL-21 pLys S) by the addition of isopropyl
-D-thiogalactoside (0.4 mM final
concentration). rSAA3 protein was purified using a Ni-NTA resin. The
eluted protein was further purified by reverse-phase
HPLC-chromatography to remove trace amounts of bacterial endotoxin. The
protein was lyophilized and resuspended in PBS at a concentration of
0.8 mg/ml. The endotoxin content of the protein was determined by the
Limulus amebocyte lysate test as described previously
(26) and was below 0.15 endotoxin units/ml. rSAA3 protein
was analyzed on an 18% SDS-polyacrylamide gel. The gels were stained
with Coomassie Blue R 250. Recombinant human A-SAA protein was
purchased from PeproTech (London, U.K.).
Induction of MMP-expression in chondrocytes
Primary chondrocytes were prepared as previously described
(26). Cells were cultured in DMEM supplemented with 5%
FCS at 37°C in a 5% CO2 atmosphere until they
were 80% confluent. Expression of MMP in chondrocytes was induced
either by 100 ng/ml SAA3 or 100 ng/ml human SAA. IL-1 (30 ng/ml) was
used as a positive control for MMP induction. After induction for the
indicated time, total RNA was prepared using the RNeasy kit (Qiagen)
according to the manufacturer’s instructions. TNF-
and IL-1 were
purchased from PeproTech.
Immunohistochemistry
Immunohistochemistry on paraffin-embedded tissue sections (nondiseased and RA synovium, and nondiseased and osteoarthritic (OA) cartilage) was performed by LifeSpan Biosciences (Seattle, WA) as described previously (20). The monoclonal anti A-SAA Ab (clone REU-82.2; Research Diagnostics, Flanders, NJ) was used as the primary Ab at dilutions of 1:10.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We identified SAA3 as the major difference product in
our study analyzing the gene expression profile in AIA. Thus we decided
to study its potential role in the disease process of induced arthritis
as a model of the human disease. A prerequisite for the further
functional characterization was to confirm the differential expression
of SAA3 in the diseased joint by an independent method.
Using RT-PCR (data not shown) and Northern blot analysis (Fig. 1
), a weak signal for SAA3
expression could be detected in the synovium isolated from the control
joint. In comparison, SAA3 mRNA expression was highly
up-regulated in the diseased synovium.
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Following the confirmation that SAA3 is up-regulated in
the diseased joint, we analyzed the spatial expression pattern of
SAA3 by in situ hybridization of whole rabbit knee joints.
SAA3 mRNA was detected in cells infiltrating into the
inflamed joint (Fig. 2, A and
B). SAA3 expression could also be detected in
areas where pannus formation starts (Fig. 2, A and
B). Furthermore, strong expression of SAA3 was
found in the meniscus and in articular chondrocytes (Fig. 2, C–E), which has not been reported before. No signal was
obtained with the sense riboprobe (data not shown). In contrast to the
Northern blot analysis, no SAA3 expression could be detected
by in situ hybridization in the control joint (data not shown).
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To confirm our results from the in situ hybridization experiment,
we isolated primary rabbit articular chondrocytes (RACs) from a healthy
animal. RACs were treated for 24 h with the indicated
concentration of IL-1, IL-1 plus TNF-, or PMA. RNA was
isolated and analyzed by Northern blot analysis, using a probe specific
for rabbit SAA3 (Fig. 3, upper panel). In resting primary chondrocytes,
SAA3 expression was below the detection limit. Upon
stimulation for 24 h with either IL-1 alone or in combination
with TNF-, SAA3 expression was strongly induced. PMA did
not induce expression of SAA3 in primary
chondrocytes.
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Previously, it was shown that SAA3 induces interstitial collagenase (MMP-1) in rabbit synovial fibroblasts in an autocrine or paracrine manner (12). Using in situ hybridization, we extended this observation and found SAA3 transcription in vivo also in rabbit chondrocytes. To directly test whether SAA3 protein can induce MMP expression in chondrocytes, we expressed recombinant rabbit SAA3 in E. coli and stimulated chondrocytes with the purified protein. The purified SAA3 protein had the expected molecular mass of 12 kDa and was over 98% homogeneous as determined by Coomassie blue staining of an 18% SDS-PAGE gel (data not shown). Purified SAA3 protein at a concentration of 100 ng/ml with an endotoxin concentration of less than 1.5 fg/ml was used for stimulation of chondrocytes. This concentration of endotoxin is significantly below MMP-inducing endotoxin concentrations in chondrocytes as previously shown (26).
rSAA3 protein is able to induce transcription of MMPs in rabbit and human chondrocytes
RACs were treated with the indicated final concentration of rSAA3
protein for the indicated time and RNA was isolated and analyzed by
Northern blot (Fig. 4A). Using
a rabbit-specific probe, MMP-13 mRNA expression was strongly increased
after 4 h decreased at 8 h and peaked again at 24 h. As
a positive control for MMP-13 expression, RACs were treated with
IL-1. The intensity of the MMP-13 transcript in cells treated with
100 ng/ml rSAA3 or 30 ng/ml IL-1 was comparable. We also examined
human articular chondrocytes (HACs) for MMP induction using rSAA3 as an
inducing agent. Similar to rabbit chondrocytes, transcription of MMP-1
was induced by 100 ng/ml rSAA3 in human primary chondrocytes 4 and
8 h after stimulation (Fig. 4B), however, less
pronounced when compared with 30 ng/ml IL-1. This may be explained
by species differences using rabbit SAA3 for the induction of human
chondrocytes. We have not been successful in detecting human MMP-13
transcripts in HACs after stimulation with rSAA3. This could reflect
the lower abundance of MMP-13 transcript in comparison to the MMP-1 RNA
in human chondrocytes.
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Because the human SAA3 is defined as a pseudogene
(4) we examined human nondiseased synovium and synovium
derived from RA patients as well as normal cartilage and OA cartilage
for expression of other members of the SAA gene family. Using a mAb
specific for acute A-SAA (detecting both SAA1 and SAA2) high levels of
A-SAA protein were detected in the inflamed synovium of RA patients
(Fig. 5B). In addition, A-SAA
protein was also detected in OA cartilage although at lower expression
levels than in the RA synovium (Fig. 5D). In nondiseased
tissue, A-SAA expression could not be detected (Fig. 5, A
and C).
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Regulation of A-SAA in chondrocytes was examined directly by
treating HACs with 30 ng/ml IL-1 for the indicated time points and
analyzing A-SAA expression by Northern blot. SAA1 and SAA2 are highly
homologous on the nucleotide level as well as on the amino acid level
(Fig. 6). Therefore, the possibility
exists that the probe used in the Northern blot analysis will not
distinguish between SAA1 and SAA2 transcripts. A-SAA transcripts were
detected after 8 h of treatment and were increasing over a 48-h
period (Fig. 6). Using RT-PCR we could amplify a single band from HACs
stimulated with IL-1 for 24 h (data not shown). Subsequently,
the PCR product was subcloned and sequenced. The sequence analysis
revealed that the PCR product was 100% identical with the previously
published sequence of SAA1 (24). Under the PCR
conditions we used, we have not been able to amplify a cDNA for
SAA2 (27, 28).
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Because the protein sequence of rabbit SAA3 and human A-SAA are
also highly homologous, we hypothesized that stimulation of HACs with
human rA-SAA might have a similar effect on MMP transcription as
stimulation of HACs with rabbit SAA3. HACs were stimulated with human
rA-SAA protein, total RNA was prepared and analyzed for MMP-1 (Fig. 7A) and MMP-13 (Fig. 7B) expression by Northern blot analysis. Normalized to the
amount of RNA loaded on the gel, as shown by staining of 28S and 18S
rRNA (Fig. 7C), no difference in MMP-1 expression between
controls and 4-h stimulated cells was observed but clearly, MMP-1 mRNA
levels are increased at 8 h before they resume to baseline levels
at 24 h (Fig. 7A). Interestingly, the signal obtained
for MMP-1 mRNA was severalfold higher at the 24-h time point when A-SAA
protein was used at a concentration of 50 µg/ml (Fig. 7A).
The latter concentration is similar to the concentration of SAA1 found
in the synovial fluid of RA patients (1). It has also been
reported that this concentration triggers chemotaxis in PMNs or
monocytes (29). This concentration of A-SAA protein also
yielded detectable MMP-13 mRNA induction (Fig. 7B). We
compared the MMP-inducing effect of A-SAA to the level of MMP induction
by IL-1 (Fig. 7C). The induction of MMP-1 transcription,
normalized to the amount of RNA loaded on the gel in IL-1 stimulated
HACs is around 2-fold more than the amount of transcripts induced by
A-SAA. A-SAA concentrations found in synovial fluid of RA patients are
significantly higher (1) than the concentration used for
stimulating HACs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As the major difference product in AIA we identified SAA3, which was confirmed by Northern blot analysis demonstrating that SAA3 transcription is augmented in the diseased rabbit synovium.
Using in situ hybridization on whole rabbit knee joints, we identified
cell type(s) expressing SAA3 in vivo. In addition to
infiltrating cells and the area where pannus formation starts,
SAA3 mRNA expression was most abundant in the tip of the
meniscus and in articular chondrocytes. Extrahepatic expression of SAA
has been described previously (5, 6, 12, 14, 15, 30, 31, 32);
however, expression of A-SAA in chondrocytes has not been described.
This novel A-SAA mRNA expression pattern was confirmed by
Northern blot analysis of isolated rabbit chondrocytes. In resting
primary chondrocytes, SAA3 expression could not be detected.
Upon stimulation with proinflammatory cytokines like IL-1 and
TNF-, SAA3 transcription is induced. In contrast to
previous results that reported PMA-inducible SAA3 expression
in synovial fibroblasts (31, 33), SAA3 could
not be induced by the same stimulus in primary rabbit chondrocytes.
Previously, SAA3 protein was shown to induce MMP-1 expression in an
autocrine manner in isolated rabbit fibroblasts (12, 31).
In extension of these studies, we showed that recombinant rabbit SAA3
protein induced transcription of MMP-13 in primary rabbit chondrocytes.
We also provide evidence for induction of MMP-1 transcription by
recombinant rabbit SAA3 in primary human chondrocytes (Fig. 4
B).
In humans, the SAA3 gene does not appear to be functional
(4). We speculated that another member of the SAA gene
family might compensate for the possible loss of a functional
SAA3 gene in human. We provide evidence using RT-PCR and DNA
sequence analysis that human chondrocytes stimulated with IL-1
express A-SAA mRNA (data not shown). Northern blot analysis showed that
A-SAA mRNA was induced by the proinflammatory cytokine IL-1 in human
primary chondrocytes. We further provide evidence by
immunohistochemistry that A-SAA is highly expressed in RA synovium,
confirming previous results showing expression of A-SAA mRNA in RA
synovial tissue and cells (14, 15). In extension of these
results we demonstrate A-SAA expression in OA cartilage. It is
important to point out that rabbit SAA3 and human A-SAA are highly
homologous at the amino acid level (Fig. 6). Moreover, in extension of
previous results (12, 34) our study provides evidence that
recombinant human A-SAA protein is able to induce transcription of
MMP-1 and MMP-13 in human chondrocytes. Similarly, it has been
demonstrated that A-SAA protein is able to induce expression of MMP-2
and MMP-3 in isolated human synovial fibroblasts (34).
Although we show in this study up-regulation of MMPs only at the RNA
level in our experimental in vitro system (rabbit and human primary
chondrocytes), we assume that the level of MMP mRNA correlates with the
amount of protein. This assumption is consistent with the generally
accepted concept that MMPs are mainly regulated on the transcriptional
level (35) as well as at the posttranslational level,
including the activation of the latent enzyme (36) and
inhibition of the activated enzyme through complex formation with
tissue inhibitors of metalloproteinases or TIMPS (37). Our
results clearly demonstrate that human A-SAA and rabbit SAA3 are
capable of inducing transcription of MMPs in chondrocytes ex
vivo.
At a concentration of 50 µg/ml, A-SAA is able to induce chemotaxis of
human macrophages, which is abrogated by the addition of pertussis
toxin, suggesting the interaction of SAA with a G protein-coupled
receptor (29). Recently formyl peptide receptor-like 1 has
been identified as the receptor mediating the chemotactic activity of
A-SAA for human phagocytic cells (38). It has also been
demonstrated that recombinant human A-SAA protein induces IL-1
synthesis in THP-1 cells at 30 µg/ml (39). In contrast,
the A-SAA concentration required to induce MMP transcription ex vivo in
chondrocytes is much lower (100 ng/ml). In this study we did not
analyze the actual levels of SAA protein produced in our tissue culture
model. However, there is data demonstrating that in the acute
inflammation phase, A-SAA serum levels can reach concentrations of up
to 2 mg/ml (40). Furthermore, the concentration of A-SAA
protein in the synovial fluid of RA patients can reach up to 50 µg/ml
(1). The concentrations found in vivo in the serum and in
the synovial fluid of RA patients are similar to the concentrations
that are able to induce chemotaxis and cytokine synthesis, and above
concentrations of A-SAA sufficient to induce MMP transcription ex vivo.
In addition to known proinflammatory cytokines such as IL-1 and
TNF- our data suggest that locally produced A-SAA may contribute to
enhanced MMP synthesis in chondrocytes and synovial fibroblasts and
could be of physiological relevance for disease progression. Thus,
interfering with A-SAA induced expression of disease relevant MMPs such
as MMP-1 and MMP-13 might open up new avenues for inhibiting
degradation of cartilage in arthritis. It was recently reported that in
the rabbit synovial fibroblast cell line HIG-82, IL-1 and IL-6
synergistically induce rabbit SAA2 expression
(41). The primary structure of the human rA-SAA protein we
used in our studies corresponds to SAA1 except the addition of a
methionine at the NH2 terminus, the substitution
of aspartic acid for asparagine at position 60 and histidine for
arginine at position 71 (Fig. 6). Although these substitutions have
previously reported to occur in natural variants of SAA proteins
(11, 42) this protein has also been classified as a hybrid
form between SAA1 and SAA2. Thus, future studies will now focus on
evaluating the relative importance of the different SAA family members
compared with each other and to other proinflammatory cytokines for
onset and progression of RA.
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Acknowledgments |
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Footnotes |
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2 Current address: Hoffmann-La Roche AG, Grenzach-Wyhlen, Germany.
3 Current address: St. Jude Medical GmbH, Nürnberg, Germany.
4 Abbreviations used in this paper: SAA, serum amyloid A; A-SAA, acute-phase SAA; AIA, Ag-induced arthritis; RA, rheumatoid arthritis; MMP, matrix metalloproteinases; OA, osteoarthritic; RDA, representational difference analysis; mBSA, methylated BSA; RAC, rabbit articular chondrocyte; HAC, human articular chondrocyte.
Received for publication March 15, 2000. Accepted for publication November 29, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2-microglobulin-like proteins. Science 243:655. alone: synthesis and secretion of ApoSAA by cultured aortic smooth muscle cells. Scand. J. Immunol. 46:284.[Medline]
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