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PubMed2004

Galectin-3: presurgical marker of thyroid follicular epithelial cell-derived carcinomas.

Preoperative follicular lesion characterisation represents an unsolved diagnostic problem in thyroid nodular disease. Although fine-needle aspiration biopsy is the most reliable preoperative diagnostic procedure, it shows inherent limitations in differentiating adenoma from follicular carcinoma and, sometimes, follicular variants of papillary carcinoma. Galectin-3 cytoplasmic neoexpression has been proposed as a peculiar feature of thyroid malignant cells, easily detectable in cytological and histological samples. The aim of this study was to re-evaluate the galectin-3 expression in a large sample of thyroid lesions using an immunohistocytochemical biotin-free detection system and a specific anti-human-galectin-3 monoclonal antibody in order to avoid the interference of technical factors, a cause of conflicting results recently reported by some authors. We analysed galectin-3 expression of 39 follicular carcinomas, 26 papillary carcinomas, and 105 adenomas in both cell-block samples and their histological counterparts. All cell-block and histological papillary carcinoma samples showed high levels of galectin-3 immunoreactivity. Thirty-four follicular carcinomas were positive, whereas 5 were negative in cell-blocks but positive in their histological counterparts. Twelve out of 105 adenomas expressed galectin-3 in cell-blocks and histological samples. The diagnostic accuracy of preoperative galectin-3 evaluation in adenomas vs follicular carcinomas was 90.0%. Galectin-3 expression was also investigated in 22 minimally-invasive follicular carcinomas. All of them showed galectin-3 immunoreactivity in both cytological and histological specimens with the exception of two cases, where galectin-3 positivity was observed only in the surgical material. The routine correct use of galectin-3, by increasing the diagnostic accuracy of conventional cytology, improves the management of thyroid nodules and can lead to a sensitive reduction of useless thyroid surgeries.

Adenocarcinoma, Follicular↗

PubMed2003

Usefulness of galectin-3 immunohistochemistry in differential diagnosis between thyroid follicular carcinoma and follicular adenoma.

Galectin-3 was primarily reported to be a marker distinguishing thyroid adenomas and carcinomas. To check the usefulness of anti-galectin-3 immunohistochemistry, we studied its expression in 42 follicular adenomas and 42 follicular carcinomas. Eight cases out of 42 follicular adenomas (19%) presented focal or diffuse galectin-3 immunoexpression. From 42 cases of follicular carcinomas, six cases did not present galectin-3 immunopositivity at all. Three of these cases were widely invasive (one with focal anaplastic feature and one oxyphilic), and three other ones were minimally invasive. Two other carcinoma cases had only small foci positive with galectin-3 antibody, thirteen cases presented positivity mostly restricted to peripheral part of the tumor and 21 cases possessed diffuse, strong reaction. Two adenomas presented galectin-3 positive foci, and these cells had light nuclear changes superficially suggesting follicular variant of papillary carcinoma, mostly because of nuclear clearing. In these tumors, adenoma diagnosis was supported by experts, but we can not exclude that they represent early phase of malignisation, although such theory needs to be prooved. Our study does not allow to use galectin-3 as a highly specific marker, differentiating between follicular benign and malignant tumor, although it may be used as an additive tool.

Adenocarcinoma, Follicular↗

PubMed2005

Phosphorylation of galectin-3 contributes to malignant transformation of human epithelial cells via modulation of unique sets of genes.

Galectin-3 is a multifunctional beta-galactoside-binding protein implicated in apoptosis, malignant transformation, and tumor progression. The mechanisms by which galectin-3 contributes to malignant progression are not fully understood. In this study, we found that the introduction of wild-type galectin-3 into nontumorigenic, galectin-3-null BT549 human breast epithelial cells conferred tumorigenicity and metastatic potential in nude mice, and that galectin-3 expressed by the cells was phosphorylated. In contrast, BT549 cells expressing galectin-3 incapable of being phosphorylated (Ser6-->Glu Ser6-->Ala) were nontumorigenic. A microarray analysis of 10,000 human genes, comparing BT549 transfectants expressing wild-type and those expressing phosphomutant galectin-3, identified 188 genes that were differentially expressed (>2.5-fold). Genes affected by introduction of wild-type phosphorylated but not phosphomutant galectin-3 included those involved in oxidative stress, a novel noncaspase lysosomal apoptotic pathway, cell cycle regulation, transcriptional activation, cytoskeleton remodeling, cell adhesion, and tumor invasion. The reliability of the microarray data was validated by real-time reverse transcription-PCR (RT-PCR) and by Western blot analysis, and clinical relevance was evaluated by real-time RT-PCR screening of a panel of matched pairs of breast tumors. Differentially regulated genes in breast cancers that are also predicted to be associated with phospho-galectin-3 in transformed BT549 cells include C-type lectin 2, insulin-like growth factor-binding protein 5, cathepsins L2, and cyclin D1. These data show the functional diversity of galectin-3 and suggest that phosphorylation of the protein is necessary for regulation (directly or indirectly) of unique sets of genes that play a role in malignant transformation.

Animals↗

PubMed1999

Sertoli cell expression of galectin-1 and -3 and accessible binding sites in normal human testis and Sertoli cell only-syndrome.

Galectins are vertebrate lectins interacting with beta-galactosides and derivates thereof such as blood group A, B and H determinants. The expression of gelectin-1 and -3 and galectin-specific binding sites by human Sertoli cells was analyzed in normal human testis and Sertoli cell only-syndrome (SCOS). Staining intensity was scored semiquantitatively on a 4-grade scale. Sertoli cells in normal testes displayed a moderate cytoplasmic and weak nuclear staining for galectin-1-specific binding sites. Galectin-3-specific binding sites were expressed in Sertoli cells less intensely than accessible ligands for galectin-1 (mean score 2.25 for galectin-1 and 1.50 for galectin-3). Germ cells were only weakly reactive. Tubular walls were negative for both classes of galectin-specific binding sites. In SCOS, galectin-1 binding was moderate to strong and more pronounced than galectin-3 binding by Sertoli cells (mean scores 4.00 and 2.25). Tubular walls were negative for galectin-staining. The ratio for galectin-1-/galectin-3-specific binding (staining score ratio) was 1.50 form normal testis and 1.78 for SCOS disclosing a relative increase of galectin-3 binding sites in the latter. Staining with galectin-1- and -3-specific antisera showed a strong cytoplasmic galectin-1 immunoreactivity in Sertoli cells of normal and SCOS testis (score 4.00 for both). Anti-galectin-3 did not stain Sertoli cells or germ cells in normal testis. Only Leydig cells were labeled (score 3.00). In SCOS a weak to moderate nuclear staining of Sertoli cells was noted (score 2.00). Galectin-3 expression and galectin-1-specific binding sites were found to be increased in Sertoli cells of SCOS. This modulation of reactivity can have implications for Sertoli cell interactions with galectin-reactive extracellular matrix components like laminin and for anti-apoptotic effects.

Adult↗

PubMed2000

Nuclear localisation of wild type and mutant galectin-3 in transfected cells.

Galectin-3, a member of a family of carbohydrate-binding proteins, is present generally in the cytoplasm of cells. However, galectin 3 can also be located in nuclei under certain conditions although it lacks any known nuclear localisation signal and the mechanism by which the protein is sequestered in nuclei is unknown. Here we describe that Cos-7 cells or rabbit smooth muscle Rb-1 cells transfected with cDNA encoding hamster galectin-3 sequester the protein in nuclei whereas untransfected BHK cells expressing the endogenous hamster lectin or transfected BHK cells over-expressing the protein, do not. Confocal immunofluorescence microscopy of Cos-7 cells or rabbit smooth muscle Rb-1 cells transfected with cDNAs encoding mutants of hamster galectin-3 containing N-terminal or internal deletions shows that nuclear localisation does not require the first 103 amino acid residues of the protein. Further deletion of residues 104-110 dramatically prevents sequestration in nuclei. However, the sequence A104PTGALT110 by itself is not obligatory for nuclear localisation and can be substituted by other unrelated sequences. A truncated galectin-3 protein, that is blocked in nuclear expression, retains carbohydrate-binding activity, making less likely the possibility that severe N-terminal truncations of galectin-3 induce mis-folding leading to aggregation and cytoplasmic sequestration and an incidental effect on nuclear trafficking. These studies indicate that nuclear import and retention of galectin-3 is a property of the CRD domain and is independent of N-terminal domains that others have shown to contain binding domains for various nuclear components.

Animals↗

PubMed2005

Mechanical entrapment is insufficient and intercellular adhesion is essential for metastatic cell arrest in distant organs.

In this report, we challenge a common perception that tumor embolism is a size-limited event of mechanical arrest, occurring in the first capillary bed encountered by blood-borne metastatic cells. We tested the hypothesis that mechanical entrapment alone, in the absence of tumor cell adhesion to blood vessel walls, is not sufficient for metastatic cell arrest in target organ microvasculature. The in vivo metastatic deposit formation assay was used to assess the number and location of fluorescently labeled tumor cells lodged in selected organs and tissues following intravenous inoculation. We report that a significant fraction of breast and prostate cancer cells escapes arrest in a lung capillary bed and lodges successfully in other organs and tissues. Monoclonal antibodies and carbohydrate-based compounds (anti-Thomsen-Friedenreich antigen antibody, anti-galectin-3 antibody, modified citrus pectin, and lactulosyl-l-leucine), targeting specifically beta-galactoside-mediated tumor-endothelial cell adhesive interactions, inhibited by >90% the in vivo formation of breast and prostate carcinoma metastatic deposits in mouse lung and bones. Our results indicate that metastatic cell arrest in target organ microvessels is not a consequence of mechanical trapping, but is supported predominantly by intercellular adhesive interactions mediated by cancer-associated Thomsen-Friedenreich glycoantigen and beta-galactoside-binding lectin galectin-3. Efficient blocking of beta-galactoside-mediated adhesion precludes malignant cell lodging in target organs.

Animals↗

PubMedDate not supplied

Immunohistochemical markers of thyroid tumors: significance and diagnostic applications.

Immunohistochemical markers of thyroid tumors can be divided into two major categories: those related to the cell types and those related to the type of pathology. The most important markers in the first category are thyroglobulin and TTF-1 for follicular cells, and calcitonin, CEA, and chromogranin for C cells. Markers in the second category are primarily directed at papillary carcinoma and include cytokeratin 19, high-molecular weight keratin (identifiable with antibody 34betaE12), S-100 protein, HBME-1, galectin 3, and p27kip1. At the practical level, cell type-related markers are much more useful than disease-related markers. Markers said to be of prognostic value in medullary carcinomas are calcitonin, bcl-2, and N-myc.

Biomarkers, Tumor↗

PubMed2003

Mechanisms involved in the stimulatory effect of advanced glycation end products on growth of rat aortic smooth muscle cells.

Hyperglycemia is an important cause of accelerated atherosclerosis in diabetic patients. We examined the effect of hyperglycemia and advanced glycation end products (AGE) on proliferation of rat aortic smooth muscle cells (SMC) in culture; in vivo, this event is believed to contribute importantly to atherogenesis in diabetes mellitus. Glucose itself dose-dependently inhibited thymidine uptake by SMC, but AGE increased thymidine uptake, suggesting that SMC proliferation is accelerated by AGE. To examine possible mechanisms for this effect, we studied nuclear factor-kappa B (NF-kappaB) activation and the tyrosine phosphorylation pathway; AGE stimulated NF-kappaB activity, but phosphorylation of the platelet-derived growth factor (PDGF) receptor was unchanged. In Chinese hamster ovary (CHO) cells overexpressing galectin-3, an AGE receptor related to atherosclerosis, AGE increased thymidine uptake. This suggests SMC proliferation is enhanced by AGE via galectin-3. As pathways involving AGE-galectin-3 interaction thus may be involved in macroangiopathy, AGE appears to be important to the role of SMC in accelerated atherosclerosis associated with diabetes mellitus.

Animals↗

PubMed2004

Galectin-3/AGE-receptor 3 knockout mice show accelerated AGE-induced glomerular injury: evidence for a protective role of galectin-3 as an AGE receptor.

We previously showed that mice lacking galectin-3/AGE-receptor 3 develop accelerated diabetic glomerulopathy. To further investigate the role of galectin-3/AGE-receptor function in the pathogenesis of diabetic renal disease, galectin-3 knockout (KO) and coeval wild-type (WT) mice were injected for 3 months with 30 microg/day of N(epsilon)-carboxymethyllysine (CML)-modified or unmodified mouse serum albumin (MSA). Despite receiving equal doses of CML, KO had higher circulating and renal AGE levels and showed more marked renal functional and structural changes than WT mice, with significantly higher proteinuria, albuminuria, glomerular, and mesangial area and glomerular sclerosis index. Renal 4-hydroxy-2-nonenal content and NFkappaB activation were also more pronounced in KO-CML vs. WT-CML. Kidney mRNA levels of fibronectin, laminin, collagen IV, and TGF-beta were up-regulated, whereas those of matrix metalloproteinase-2 and -14 were down-regulated, again more markedly in KO-CML than WT-CML mice. Basal and CML-induced RAGE and 80K-H mRNA levels were higher in KO vs. WT mice. MSA injection did not produce any significant effect in both genotypes. The association of galectin-3 ablation with enhanced susceptibility to AGE-induced renal disease, increased AGE levels and signaling, and altered AGE-receptor pattern indicates that galectin-3 is operating in vivo as an AGE receptor to afford protection toward AGE-dependent tissue injury.

Aldehydes↗

PubMed1998

Invasion potential and N-acetylgalactosamine expression in a human melanoma model.

Reactivity of the N-acetylgalactosamine-binding Helix pomatia agglutinin (HPA) in tumours has been associated with poor prognosis and metastasis development. In our LOX/FEMX-I human melanoma model, the binding of HPA correlates with experimental lung metastasis formation in athymic nude mice. In the present study, the metastatic potential of 2 human melanoma cell lines (LOX and FEMX-I) was assessed in relation to carbohydrate and invasive phenotype. Immunocytological and invasion assays highlighted significant differences between these 2 cell lines. Immuno-cytochemical analysis confirmed the widespread expression of HPA-binding glycoconjugates on LOX but not FEMX-I cells. One of these HPA-binding glycoconjugates, the Tn antigen, was expressed highly on the surface of LOX cells but only weakly in the cytoplasm of FEMX-I cells. The sialyl Tn antigen was expressed in FEMX-I but not in LOX cells. There was no difference between the cell lines in adhesion/rate of trapping in athymic nude mouse lung tissues. In Matrigel invasion assays, LOX cells demonstrated an invasion potential more than 6 times greater than that observed with FEMX-I cells. Matrigel invasion of LOX cells was inhibited after incubation with HPA (89%) compared to controls with HPA and GalNAc blocking sugar or without HPA (p < 0.0005 at 5 df). In contrast, there was no inhibitory effect with the anti-Tn antibody IE3. Invasion of FEMX-I cells was not affected by the lectin and the IE3 antibody. Immuno-cytochemical analysis revealed expression of the terminal galactose- and polylactosamine-binding lectin galectin 3 (Mac-2) in these melanoma cell lines. Expression of both the lectin and its receptor may be a contributory feature in the pulmonary invasion of LOX melanoma cells. Overall, our findings suggest that HPA-binding glycoconjugates other than the alphaGalNAc-O-Ser/Thr of the Tn antigen may be important in the extracellular matrix invasion of LOX melanoma cells.

Acetylgalactosamine↗

PubMed1999

Simultaneous detection of endogenous lectins and their binding capacity at the single-cell level--a technical note.

Endogenous lectins are proteins/glycoproteins which selectively recognize distinct saccharide ligands and are different from immunoglobulins and carbohydrate-utilizing enzymes. Expression of these molecules can be detected immunohistochemically using nonblocking monoclonal antibodies (A1D6: anti-galectin-3, MR-15-2-2: anti-175 kD mannose receptor). Alternatively, biotinylated (neo)glycoconjugates which are recognized by a studied lectin can be employed as convenient probes to demonstrate specific binding of sugar epitopes by carbohydrate recognition domains (CRD) of endogenous lectins. In this study, we describe a new procedure for immunocytochemical visualization of the expression of endogenous lectins and glycochemical visualization of the reactivity of carbohydrate recognition domain(s), performed simultaneously at the single-cell level.

Animals↗

PubMed2000

Biologic instability of pancreatic cancer xenografts in the nude mouse.

Tumor transplants into nude mice (NM) may reveal abnormal biological behavior compared with the original tumor. Despite this, human tumor xenografts in NM have been widely used to study the biology of tumors and to establish diagnostic and therapeutic modalities. Clearly, precise differences in the biology of a given tumor in human and in NM cannot be assessed. We compared the growth kinetics, differentiation pattern and karyotype of an anaplastic Syrian hamster pancreatic cancer cell line in NM and in allogenic hamsters. As with the original tumor, transplants in hamsters grew fast, were anaplastic and expressed markers related to tumor malignancy like galectin 3, TGF-alpha and its receptor EGFR at high levels. However, tumors in the NM were well-differentiated adenocarcinomas, grew slower, had increased apoptotic rate and had a high expression of differentiation markers such as blood group A antigen, DU-PAN-2, carbonic anhydrase II, TGF-beta(2) and mucin. Karyotypically, the tumors in the NM acquired additional chromosomal damage. Our results demonstrate significant differences in the morphology and biology of tumors grown in NM and the allogenic host, and call for caution in extrapolating data obtained from xenografts to primary cancer.

Animals↗

PubMedDate not supplied

Circulating IgG response to stromelysin-3, collagenase-3, galectin-3 and mesothelin in patients with pharynx/larynx squamous cell carcinoma.

With the aim of identifying tumor-associated antigens that could be potential markers and/or targets of diagnostic and/or therapeutic approaches, we studied the occurrence of circulating IgG antibodies to human stromelysin-3, collagenase-3, galectin-3 and mesothelin, by Western blot against their purified recombinant forms, in the sera of 50 patients with pharynx/larynx squamous cell carcinoma (PLSCC), as well as in the sera of 50 healthy blood donors. Overall, antibodies to collagenase-3 were detected in 50% of all the cancer patients and 16% of the blood donors examined; this percentage difference was statistically significant (p = 0.00066). With respect to anti-galectin-3 antibodies, the percentages were 32% and 18%, respectively, but they were not statistically different (p = 0.16). Low levels of antibodies to stromelysin-3 and to mesothelin were detected in sera from only two cancer patients. No significant correlations were found in the present study between the presence of antibodies to these proteins and tumor site, clinical and T stages, lymph node involvement, DNA ploidy and histological grade of differentiation of the primary tumors. To our knowledge, this is the first report on the detection of circulating IgG to collagenase-3 in cancer patients. Some of the percentages found here in certain groups of patients are among the highest reported of circulating antibodies to any tumor component studied so far. The monitoring and the use of human antibodies to collagenase-3 could be of diagnostic and therapeutic interest.

Adult↗

PubMed2002

High-affinity binding of recombinant human galectin-4 to SO(3)(-)-->3Galbeta1-->3GalNAc pyranoside.

Galectin-4 is a member of galectin family and has two carbohydrate recognition domains. Although galectin-4 has been thought to function in cell adhesion, its precise carbohydrate binding specificity has not yet been clarified. We studied the carbohydrate binding specificity of galectin-4 comparatively with that of galectin-3, using surface plasmon resonance, galectin-3- or -4-Sepharose column chromatography and the inhibition assay of their binding to immobilized asialofetuin. Galectin-3 broadly recognized lactose, type 1, type 2, and core 1. The substitution at the C-2 and C-3 position of beta-galactose in these oligosaccharides with alpha-fucose, alpha-GalNAc, alpha-Neu5Ac, or sulfate increased the binding ability for galectin-3, whereas the substitution at the C-4 or C-6 position diminished the affinity. In contrast, galectin-4 had quite weak affinity to lactose, type 1, and type 2 (K(d) congruent with 8 x 10(-4) M). Galectin-4 showed weak binding ability to core 1 and C-2' or -3'-substituted lactose, type 1, and type 2 with alpha-fucose, alpha-GalNAc, or sulfate (K(d) : 5 x 10(-5) approximately 3 x 10(-4) M). Interestingly, the K(d) value, 3.4 x 10(-6) M, of SO(3)(-)-->3Galbeta1-->3GalNAc-O-Bn to galectin-4 at 25 degrees C was two orders of magnitude lower than that of core 1-O-Bn. 3'-Sialylated core 1 had very weak affinity to galectin-4, suggesting that 3'-O-sulfation of core 1 is critical for the recognition. These results suggest that galectin-4 has a unique carbohydrate binding specificity and interacts with O-linked sulfoglycans.

Antigens, Differentiation↗

PubMed2005

Decreased relative expression level of trefoil factor 3 mRNA to galectin-3 mRNA distinguishes thyroid follicular carcinoma from adenoma.

The expression level of trefoil factor 3 (TFF3) mRNA is a marker for distinguishing thyroid follicular adenomas from carcinomas. However, when measuring the expression level of TFF3 mRNA in fine needle aspiration biopsies, an appropriate internal control mRNA, of which expression is restricted in thyroid epithelial--derived cells, is necessary, since they are often contaminated with a considerable number of blood cells, which do not express TFF3 mRNA. In this study, we evaluated the efficiency of molecular-based diagnosis of thyroid follicular carcinoma by measuring the relative expression of TFF3 mRNA by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) using galectin-3 mRNA as an internal control. The TFF3/galectin-3 mRNA ratio (T/G ratio) was measured in 54 follicular adenomas and 29 follicular carcinomas. It was markedly decreased in 7 follicular carcinomas of widely invasive type and with evident distant metastases. When the cutoff point was set at 16.0 by a receiver operator characteristic curve, the TG ratio showed good agreement with the pathological diagnosis [kappa=0.55; 95% confidence interval (CI), 0.34-0.77]. This agreement was better when the pathologically questionable cases were excluded (kappa=0.72; 95% CI, 0.49-0.95). Quantification of the T/G ratio may be a useful tool for the distinction between follicular adenomas and carcinomas, which is the most difficult in thyroid pathology.

Adenocarcinoma, Follicular↗

PubMed2002

Roles of galectins in vivo.

The mutational analysis of the galectin family is shedding a different light of this class of molecules. On the one hand, it appears that galectin 1 and galectin 3 are not required for the survival of mice in normal animal house conditions, while on the other hand, there seems to be several subtle, but very complex, consequences of lacking galectins during development.

Animals↗

PubMed2003

Functional characterization of adherent synovial fluid cells in rheumatoid arthritis: destructive potential in vitro and in vivo.

OBJECTIVE: To characterize the morphologic and immunologic features of adherent synovial fluid cells derived from patients with rheumatoid arthritis (RA), and to explore their potential function in vitro and in vivo by focusing on cartilage destruction. METHODS: Synovial fluid adherent cells obtained from patients with RA and from control subjects were characterized by immunohistochemistry, flow cytometry, and electron microscopy. In vitro, these cells were cultured in the presence of cartilage particles. Cartilage destruction was monitored by the release of sulfated glycosaminoglycans (sGAG) into the medium, and the level of matrix metalloproteinase 1 (MMP-1) in the cell culture supernatant was measured by enzyme-linked immunosorbent assay. To inhibit cartilage destruction in vitro, the MMP inhibitor marimastat was tested in this system. In vivo, in the SCID mouse coimplantation model, RA synovial fluid adherent cells and RA synovial fibroblasts (as positive controls) were coimplanted with human cartilage under the kidney capsule and maintained there for 60 days. RESULTS: In vitro, the synovial fluid adherent cells consisted of 2 subpopulations, large round-shaped macrophage-like cells (CD68+) and spindle-shaped fibroblast-like cells (Thy-1+). When passaged, the latter cells proliferated and organized themselves into 3-dimensional formations. This allowed them to reach collagen particles fixed with agarose. Fibroblasts derived from synovial tissues could not be used in this assay because they grew only in monolayers and not on agarose. The majority (>90%) of passaged RA synovial fluid adherent cells expressed the Thy-1+,CD45-,CD68-,CD86- phenotype. Electron microscopy did not reveal important morphologic differences between the 2 types of fibroblasts, those from synovial tissue or those from synovial fluid. However, synovial fluid adherent cells expressed lower levels of adhesion molecules, including CD54 and galectin 3, as well as the complement-regulatory molecule CD55. The in vitro release of sGAG associated with cell activity was 2.5-fold higher from RA synovial fluid adherent cells in comparison with that from negative control cells. The release of sGAG correlated with the concentration of MMP-1 and was inhibited by the broad-range MMP inhibitor marimastat in a dose-dependent manner. RA synovial fluid adherent cells coimplanted with cartilage in SCID mice showed the same invasive behavior as that displayed by tissue-derived RA synovial fibroblasts. CONCLUSION: Similar to tissue-derived RA synovial fibroblasts, RA synovial fluid adherent cells, which contain "floating" anchorage-independent fibroblast-like cells, mediate cartilage destruction independent of the hyperplastic synovial tissue.

Adult↗

PubMed1996

Monoclonal antibodies as tools for studying the osteoblast lineage.

Knowledge of the number and kinds of differentiation steps characterizing cells of the osteoblast lineage is inadequate. To analyze further osteoblast differentiation, a number of labs have generated monoclonal antibodies to osteogenic cells, derived from both normal bone and osteosarcomas. A variety of immunolabelling patterns on primary cell cultures, cell lines, and tissue sections has been reported, including cell surface, cytoplasmic, and extracellular matrix-associated patterns. Most of the antibodies selected recognize predominantly the mature osteoblast and osteocyte; in addition, however, antibodies have been generated that recognize pre-osteoblasts. Some recognize cells of both the osteoblast and chondroblast lineages and may contribute to a better understanding of the lineage and phenotypic relationships between these two cell types. In addition to recognition in vivo of cell subpopulations of discrete maturational stages, changes in the immunolabelling patterns in vitro have also documented a differentiation sequence in cells undergoing osteogenesis in cell and tissue cultures. In at least two cases, the antibodies have been used to isolate subpopulations of cells from bone, including relatively pure populations of osteocytes. With the exception of several antibodies that are against alkaline phosphatase or known matrix proteins including osteocalcin, the nature of the macromolecular species recognized by most of the antibodies generated to date are unknown. Recently, however, one antibody was used to clone the cDNA for the beta-galactoside-binding lectin, galectin 3 or epsilon binding protein (epsilon BP; IgE-binding protein; Mac-2), from a lambda gt11 osteoblast expression library; another was used to clone from an ROS 17/2.8-COS cell expression library the cDNA for OTS-8, a putative target gene of early response genes stimulated in response to phorbol esters in MC3T3-E1 cells. Neither of these macromolecules had previously been identified in bone cells, but the recent molecular and cellular analyses have shown them to be developmentally and/or hormonally regulated in osteoblastic cells. These antibodies extend the available markers and support earlier observations that a variety of molecules are differentially expressed by cells at different stages of the osteoblast lineage. This chapter will not be an exhaustive survey of all immunocytochemical and immunohistochemical analyses of osteogenic cells and tissues but will focus on the approach of eliciting novel monoclonal antibodies by the injection of osteogenic cells or crude bone extracts and its potential for establishing new markers of the osteoblast lineage. We have not included a large number of studies documenting the use of antibodies raised against several known bone matrix proteins; while these have been crucial in developing our current understanding of osteogenic differentiation, we sought rather to highlight the potential of the "random" injection approach.

Animals↗