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RESEARCH REPORT |
Craniofacial and Skeletal Diseases Branch, Building 30, Room 228, National Institute of Dental and Craniofacial Research, National Institutes of Health, DHHS, 9000 Rockville Pike, Bethesda, MD 20892-4320, USA;
* corresponding author, lfisher{at}dir.nidcr.nih.gov
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: SIBLING • MMP • bone sialoprotein • osteopontin • dentin matrix protein-1
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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With the clear exception of osteopontin, the SIBLINGs are generally reported to be limited to bones and teeth in normal adults. OPN was reported in normal, non-mineralizing tissues, including: kidney (Shiraga et al., 1992), lactating breast (Senger et al., 1989), and immune cells (Patarca et al., 1990). A 1992 report by Brown et al. noted the presence of OPN in several epithelial tissues, including salivary glands. In contrast, Kusafuka et al.(1999) noted that OPN was not expressed in salivary glands. BSP, originally found in bones and dentin (Fisher et al., 1983), was reported to be expressed by trophoblasts (Bianco et al., 1991) and ameloblasts (Chen et al., 1998). DMP1 was initially thought to be dentin-specific (George et al., 1995), but its mRNA has been found in bones (MacDougall et al., 1998), the brain (Hirst et al., 1997), and ameloblasts (George et al., 1995). DSPP was also originally thought to be limited to dentin, but low levels of expression have been described in bones (Qin et al., 2002) and ameloblasts (D’Souza et al., 1997). The original publication of MEPE indicated, by RT-PCR, low levels in the normal adult brain and kidney in addition to higher levels in bones (Rowe et al., 2000).
We have recently shown that BSP, DMP1, and OPN each binds with high affinity (nM) and specifically activates proMMP-2, proMMP-3, and proMMP-9, respectively. Furthermore, the SIBLINGs can specifically re-activate their corresponding TIMP-inhibited MMPs (Fedarko et al., 2004), and BSP has been shown to enhance invasion in vitro by bridging MMP-2 to the cell surface via the 
vß3integrin (Karadag et al., 2004). Thus, the expression of a SIBLING protein with or even near a source of its MMP partner can result in active proteases and local processing of proteins. It is not known if DSPP and MEPE also have MMP partners.
Our hypothesis is that documentation of the co-expression of SIBLINGs and their specific MMP partners in normal, non-mineralizing tissues will suggest that the SIBLINGs have functions other than direct control of mineralization.
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MATERIALS & METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Antibody Production
The monoclonal and polyclonal antisera used for this study are listed (Table
). We made new antibodies using standard mouse hybridoma technology (Maine Biotechnology Services, Portland, ME, USA) and in New Zealand white rabbits (Covance, Denver, PA, USA) using approved animal care protocols at the contract facilities. The antigens were as follows: LFMb-25, human BSP amino acids 159-317 (with additional cysteine at the amino terminus for conjugation to maleimide-activated keyhole limpet hemocyanin, KLH; Pierce, Rockford, IL, USA) was made as a His6-fusion protein in E. coli and purified on His-Bind resin (Novagen, Madison, WI, USA). Full-length mouse OPN (LF-175), human OPN (LFMb-14) (amino acids 159-300), and mouse DSPP (LF-153, amino acids 49-363) were made as His6-fusion proteins in bacteria, purified, and directly used as antigens. Monoclonals to human MEPE (LFMb-33, amino acids 42-525) and DMP1 (LFMb-31, amino acids 62-513) His6-fusion proteins were conjugated through amino groups to EDC-activated KLH (Pierce). All synthetic peptides were conjugated to maleimide-KLH. MMP antibodies were from commercial sources (Table).
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). Negative controls included non-immune serum for rabbit antisera and IgG-isotype controls for monoclonals.
Preparation and Detection of RNA Probes
A summary of the sense and antisense riboprobes used for human and mouse SIBLINGs and MMPs is shown (Table). Human SIBLING probes were used on monkey sections. Full-length human MEPE cDNA was made by PCR with the use of a brain cDNA template (Multiple Tissue cDNA Panel, #1420-1, BD Bioscience, Palo Alto, CA, USA). The final product was cloned into pBluescript-KS (Stratagene, La Jolla, CA, USA). For all other PCR-based probes, the purified PCR products were digested with the appropriate restriction enzymes engineered into the oligonucleotides and cloned into PCR-II (mop-3 and mBSP1, Invitrogen, Carlsbad, CA, USA) or pBluescript-SK. PCR oligonucleotides are listed (Table). Clones were verified by DNA sequencing.
Both sense and antisense probes were labeled with use of the Digoxigenin (DIG) RNA-Labeling Mix (Roche, Mannheim, Germany) and the appropriate RNA-polymerases. The amount of DIG-labeled control (sense) probe used was always greater than that used for the antisense (as determined by comparison of serial-dilution dot blots on charged nylon membranes). In situ detection was by the InnoGenexTM Universal-ISH-BCIP/NBT Kit (Innogenex, San Ramon, CA, USA).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Osteopontin and its partner MMP-3 were co-localized at both the protein and mRNA levels in primates and mouse salivary glands. In humans, OPN (Figs. 1A–1C) and MMP-3 (Figs. 1D, 1E) were present throughout the entire ductal system (intercalated, striated, excretory ducts), as shown by immunohistochemistry and in situ hybridization, but were absent in both serous and mucous acini. Within the striated ducts, OPN immunoreactivity was distinctly more prominent in the basal half, in direct association with the striations and cell junctions (Fig. 1B). Occasional cells within the striated ducts that were devoid of both striations and contact with lumen (sometimes known as basal cells) appeared free of both OPN protein and message (Figs. 1B, 1E, black arrows), suggesting that only mature ductal cells express the 2 proteins. Like the primates, ductal segments of mouse major glands expressed OPN (Figs. 1G–1J) and MMP-3 (Fig. 1K), except for the unique granular convoluted tubule (GCT, noted by * in several panels), which did not express either gene product (Figs. 1J, 1K). Although mouse OPN was often associated with the distinctive basal striations, this pattern was less prominent than in the primates. In contrast to primates, however, mouse OPN (Figs. 1G–1J) and MMP-3 (Fig. 1K) also were observed in the seromucous acini of the submandibular gland and serous acini of the parotid gland. Controls for both immunostaining and in situ were uniformly negative and are represented by IgG control (Fig. 1F) and sense strand (Fig. 1L), respectively.
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, 2B), DMP1 (Figs. 2G, 2H), DSPP (DSP domain, Figs. 3A, 3B, with DPP domain not shown), and MEPE (Figs. 3C, 3D)—in human salivary glands by both antisera and in situ were the same as that for OPN. They were expressed throughout the length of the duct systems with uniformly negative acini. As was observed with OPN, occasional primate ‘basal’ cells located within a duct were negative for both protein and mRNA for these 4 SIBLINGs (e.g., Fig. 2B, black arrow). However, unlike the basal distribution of OPN, all other SIBLINGs exhibited a more even basal-luminal distribution within the striated duct cells. MMP-2 and MMP-9 co-localized with their partner SIBLINGs, BSP and DMP1, respectively, in each gland, including a general lack of staining in the ‘basal’ cells (in situ data are shown; Figs. 2C, 2I). Most of the sections did not have obvious duct luminal contents; however, when present, they tended to stain positive for the SIBLINGs, suggesting at least some secretion into the lumen (data not shown).
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, 2E) and DMP1 (Figs. 2J, 2K), as well as MEPE in situ (Fig. 3F), mirrored that of mouse OPN (see Figs. 1G, 1H). They were present in both the non-GCT ductal elements and seromucous acini. Interestingly, mouse DSPP immunolocalization (Fig. 3E) was more like that of primate SIBLINGs, being found only in the ductal system (non-GCT) and not in the acini. In the mouse, the MMPs continued always to co-localize with their SIBLING partners—MMP-2 (Fig. 2F) with BSP, MMP-3 (Fig. 1K) with OPN, and MMP-9 (Fig. 2L) with DMP1. As in the primates, the mouse MMPs were observed only in cells that also expressed their partner SIBLING. Although not shown, human minor salivary glands had the same staining patterns as the major glands for all 8 gene products. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Our results confirm those of Brown et al.(1992), who showed OPN expression in ductal elements of human salivary glands, although, in all 3 species, we saw intense basal staining patterns in the striated ducts rather than the luminal pattern suggested by those authors. The expressions of BSP, DMP1, DSPP, and MEPE were essentially uniform throughout the cells of the entire ductal system of primate salivary glands. The same expression pattern within the ducts was seen for mice, except that none of the SIBLINGs was expressed in the male mouse’s granular convoluted tubule (GCT) segments. This prominent segment of the rodent submandibular duct system is a unique, androgen-dependent structure and is known to produce several bioactive compounds (Pinkstaff, 1998). Primates do not have an equivalent of the GCT within their salivary duct system. Although the overall intensity of duct cell immunoreactivity and mRNA signals varied slightly among the SIBLINGs, no consistent differences between segments of the ductal system (intercalated, striated, and interlobular) were apparent in the primate glands. What is particularly interesting is that in mice, but not in primates, all of the SIBLINGs except DSPP were also expressed in the serous acini of the parotid and the seromucous acini of the submandibular glands.
In all 3 species, MMP-2, MMP-3, and MMP-9 were shown to co-localize in the mature ductal cells with their partner SIBLINGs (BSP, OPN, and DMP1, respectively). The mouse salivary glands were particularly revealing in this respect, because, like the SIBLINGs, the messages for the 3 MMPs were invariably missing in the GCT of the male mouse ductal system. Furthermore, these 3 SIBLINGs and their partner MMP mRNAs were uniquely found in the acini of the rodent. These observations provide convincing evidence that the SIBLING-MMP pairing described in vitro may also be important in vivo. Recently, others have independently verified, by immunohistochemistry, that MMP-2 and MMP-9 (MMP-3 was not reported) are expressed in the ducts, but not the acini, of normal human salivary glands (Nagel et al., 2004). Interestingly, they also showed the same expression pattern of the tissue inhibitors of matrix metalloproteinases, TIMPs. Previously, we have shown in vitro that the appropriate SIBLING partner will re-activate a TIMP-inactivated MMP upon binding (Fedarko et al., 2004), thereby suggesting that the MMPs may remain active in the ducts/saliva, even in the presence of these inhibitors.
Numerous earlier reports have shown the up-regulation of the SIBLINGs in several different tumors (Bellahcéne et al., 1996; Waltregny et al., 1998; Chaplet et al., 2003). Because most aggressive tumors are associated with the up-regulation of MMP-2, MMP-3, and/or MMP-9, the SIBLING-MMP complexes may aid the metastatic processes of tumor cells. Indeed, we have recently shown that BSP enhances the invasion potential of many different cancer cell lines by bridging MMP2 to the vß3 integrin (Karadag et al., 2004). Within growing bones and teeth, these same complexes could logically be hypothesized to be involved in the processing of proteins, thereby aiding the maturation of the matrix prior to mineralization. However, because the ductal cells in adult salivary glands are immobile and unlikely to be degrading connective tissue (or basement membranes), as would metastatic cancer cells, it is possible that the SIBLING/MMP complexes are involved in the normal turnover of cell-surface and/or pericellular matrix proteins damaged by oxidative by-products of these metabolically active cells. Indeed, since osteoblasts and odontoblasts are cells with an extremely high metabolism, they may also require proteolytic activity to maintain their local micro-environment. Finally, because MMPs are known to be secreted in the saliva (Wu et al., 1997), it is possible that specific salivary proteins are processed by these complexes as they move down the ducts and/or within the environment of the mouth.
In summary, all SIBLINGs and their MMP partners were co-expressed in the salivary ducts of all 3 species, except the GCT ducts of male mice. In mice, all of the SIBLINGs except DSPP were also expressed in the serous acini of the parotid and seromucous acini of the submandibular gland. Due to the high (nM) affinity and specificity of the interactions between the SIBLING-MMP partners (Fedarko et al., 2004), only the correct complexes will likely form upon co-secretion, even though all of the proteins are present. Three future challenges include: (1) finding possible MMP partners for DSPP and MEPE; (2) identifying the specific protein substrates of the SIBLING-MMP complexes; and (3) determining the balance between inhibition by TIMPs and activation by SIBLINGs in different tissues.
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ACKNOWLEDGMENTS |
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Received October 8, 2003; Last revision June 25, 2004; Accepted June 29, 2004
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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