Biomedical subjects

K Heikinheimo

Publications and source records attributed to K Heikinheimo.

At least 19 recordsLinked to original sources

PubMed2003

A case of multiple AOT-like jawbone lesions in a young patient--a new odontogenic entity?

We assessed the immunohistochemical profile of an unusual case of multiple similarly looking tumors in the jawbone of a young patient. Histologically, the tumors exhibited features of adenomatoid odontogenic tumor (AOT) and adenomatoid dentinoma but showed no resemblance to any other defined odontogenic tumor entities. They expressed high amounts of cytokeratin (CK) 8 and 14 together with some Vimentin. A small rim of peripheral cells showed CK 5, 17, and 19 reactivity. Also, these lesions expressed some bcl-2 as well as p53 and Ki67. Histologically and immunohistochemically, the unusual multiple lesions differed in details from a simultaneously examined group of 24 classical AOT cases, suggesting that they may represent a hitherto less well-defined odontogenic tumor entity.

Antigens, Neoplasm↗

PubMed2003

Different mechanisms of syndecan-1 activation through a fibroblast-growth-factor-inducible response element (FiRE) in mucosal and cutaneous wounds.

Syndecan-1 expression is enhanced in cutaneous and mucosal wounds. We have previously demonstrated that wounding-induced syndecan-1 expression in the skin occurs transcriptionally, through a fibroblast-growth-factor-inducible element (FiRE). Here, we show that FiRE is also activated in mucosal wounds. However, both the expression patterns and the activation mechanisms of FiRE are different from those in the skin. In the mucosa in vivo, the activation starts and ends earlier than in cutaneous wounds. FiRE is first detected at around 12 hours in keratinocytes, and the activation declines by the third day after wounding occurs. The activation is seen on the migrating sheet of epithelial mucosa, as in the case of cutaneous wounding. In contrast to the situation in vivo, organ-cultured mucosal wounds exhibit no FiRE activity, while organ-cultured cutaneous wounds show robust activity. Activation in mucosal wounds is enhanced, however, by the application of epidermal growth factor. This suggests that exogenous growth factor activity is required for activation of syndecan-1 in mucosal wounds but not in cutaneous wounds.

Animals↗

PubMed2002

Gene expression profiling of ameloblastoma and human tooth germ by means of a cDNA microarray.

The molecular and genetic characteristics of ameloblastoma are still poorly understood. We analyzed gene expression in fresh-frozen ameloblastomas and human fetal tooth germs, using a cDNA microarray. Thirty-four genes exhibited significant changes in expression levels in the ameloblastoma. Eleven genes were overexpressed more than three-fold, and 23 genes were underexpressed to below 0.4 of the control level. The oncogene FOS was the most overexpressed gene (from eight- to 14-fold), followed by tumor-necrosis-factor-receptor 1 (TNFRSF1A). Genes for sonic hedgehog (SHH), TNF-receptor-associated-factor 3 (TRAF3), rhoGTP-ase-activating protein 4 (ARHGAP4), deleted in colorectal carcinoma (DCC), cadherins 12 and 13 (CDH12 and 13), teratocarcinoma-derived growth-factor-1 (TDGF1), and transforming growth-factor-beta1 (TGFB1) were underexpressed in all tumors. In selected genes, a comparison between cDNA microarray and real-time RT-PCR confirmed similar relative gene expression changes. The gene expression profile identifies candidate genes that may be involved in the origination of ameloblastoma and several genes previously unidentified in relation to human tooth development.

Adolescent↗

PubMed2001

The human tuftelin gene: cloning and characterization.

Tuftelin has been suggested to play an important role during the development and mineralization of enamel. We isolated the full-length human tuftelin cDNA using reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (5' RACE and 3' RACE) methods. Sequence analysis of the tuftelin cDNA revealed an open reading frame of 1170 bp encoding a 390 amino acid protein with a molecular mass of 44.3 kDa and an isoelectric point of 5.7. The human tuftelin protein shares 89 and 88% amino acid sequence identity with the bovine and mouse tuftelin, respectively. It contains a coiled-coil region, recently reported to be involved with tuftelin self-assembly and with the interaction of tuftelin with TIP39 (a novel tuftelin interacting protein). Detailed DNA analysis of the cloned genomic DNA revealed that the human tuftelin gene contains 13 exons and is larger than 26 kb. Two alternatively spliced tuftelin mRNA transcripts have now been identified in the human tooth bud, one lacking exon 2, and the other lacking exon 2 and exon 3. Primer extension analysis, corroborated by RT-PCR and DNA sequencing, revealed multiple transcription initiation sites. The cloned 1.6 kb promoter region contained several GC boxes and several transcription factor binding sites such as those for activator protein 1 and stimulatory protein 1. Our blast search of the human and mouse expressed sequence tag data bases, as well as our RT-PCR and DNA sequencing results, and a previous study using Northern blot analysis revealed that tuftelin cDNA sequences are also expressed in normal and cancerous non-mineralizing soft tissues, suggesting that tuftelin has a universal function. We have now identified and characterized different alternatively spliced mouse tuftelin mRNAs in several non-mineralizing tissues. These results provide an important baseline for future understanding of the biological role of tuftelin.

5' Flanking Region↗

PubMed2001

The role of effectors of the activin signalling pathway, activin receptors IIA and IIB, and Smad2, in patterning of tooth development.

The gene for activin betaA is expressed in the early odontogenic mesenchyme of all murine teeth but mutant mice show a patterning defect where incisors and mandibular molars fail to develop but maxillary molars develop normally. In order to understand why maxillary molar tooth development can proceed in the absence of activin, we have explored the role of mediators of activin signalling in tooth development. Analysis of tooth development in activin receptor II and Smad2 mutants shows that a similar tooth phenotype to activin betaA mutants can be observed. In addition, we identify a novel downstream target of activin signalling, the Iroquois-related homeobox gene, Irx1, and show that its expression in activin betaA mutant embryos is lost in all tooth germs, including the maxillary molars. These results strongly suggest that other transforming growth factor beta molecules are not stimulating the activin signalling pathway in the absence of activin. This was confirmed by a non-genetic approach using exogenous soluble receptors to inhibit all activin signalling in tooth development, which reproduced the genetic phenotypes. Activin, thus, has an essential role in early development of incisor and mandibular molar teeth but this pathway is not required for development of maxillary molars.

Activin Receptors, Type II↗

PubMed1999

Localization of growth differentiation factor-9 (GDF-9) mRNA and protein in rat ovaries and cDNA cloning of rat GDF-9 and its novel homolog GDF-9B.

Although targeted gene disruption of GDF-9, an oocyte derived growth factor, leads to an arrest of folliculogenesis and causes infertility in female mice, little is known on the expression of GDF-9 protein in the ovary. We show that GDF-9 protein is expressed in rat oocytes during folliculogenesis from the early primary follicle stage onwards but the most intensive immunostaining was seen in primary and preantral follicles. Northern blot analyses of the ontogeny of GDF-9 gene expression in postnatal rat ovaries showed that the GDF-9 transcript levels are clearly increased on the second postnatal day concomitant with the appearance of primary follicles. Interestingly, Northern blot and in situ hybridization analyses indicate a similar expression pattern for GDF-9B, the rat ortholog of a mouse GDF-9 like factor for which we recently reported the partial amino acid sequence. The polypeptide sequences deduced from isolated ovarian cDNAs indicate that the rat GDF-9 prepropeptide is 440 amino acids (aa) in length and the putative mature peptide is 135 aa whereas rat GDF-9B is 391 aa long and the mature region is 125 aa. We conclude that (1) the GDF-9 protein is highly expressed in the oocytes of primary follicles of rat ovaries suggesting that it plays a role mainly in early folliculogenesis and that (2) the full-length polypeptide sequence of GDF-9B suggests that this novel TGF-beta family member is likely to be a secreted growth factor that may regulate folliculogenesis at similar developmental stages as GDF-9.

Aging↗

PubMed1999

Expression of laminin-5 in ameloblastomas and human fetal teeth.

Extracellular matrix proteins have been shown to play important roles in the cell migration and differentiation in both normal and pathological conditions. In the present study, we used immunohistochemistry and in situ hybridization to determine the distribution of laminin-5 in ameloblastomas and developing human teeth. In ameloblastomas, the immunoreaction for the laminin-5 gamma2 chain was confined to the tumor cells of the peripheral area. The staining reaction was variable, being mostly weak and fragmented in the basement membrane structures surrounding the neoplastic islands. Some peripheral epithelial cells and some invading small ameloblastoma cell islands showed intense intracellular staining for the gamma2 chain. Tumor cells in the proliferating areas of ameloblastomas expressed gamma2 chain mRNA. The laminin-5 gamma2 chain was located beneath the dental lamina and in the outer, but not in the inner, enamel epithelium of the developing teeth. During the early hard tissue apposition stage, intense staining for the gamma2 chain was confined to ameloblasts, which also gave a strong signal for gamma2 chain mRNA. These results suggest that laminin-5 may contribute to the infiltrative and progressive growing potential of ameloblastomas. During human tooth development, however, laminin-5 may participate in the terminal differentiation of ameloblasts and in enamel matrix formation.

Ameloblastoma↗

PubMed1998

Activin and bone morphogenetic protein (BMP) signalling during tooth development.

Activins and bone morphogenetic proteins (BMPs) belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related cytokines. Results of recent in vivo and in vitro studies suggest that activin A, several BMPs, and their cell surface receptors may participate in tooth development. In addition, follistatin an extracellular protein that may interact with activin and BMP signaling, appears to be involved. This review focuses on recent advances in relation to the roles of activin/BMP receptors, their ligands and extracellular modifiers during tooth development.

Activin Receptors↗

PubMed1997

An open clinical trial of a new mouth-PUVA variant in the treatment of oral lichenoid lesions.

OBJECTIVE: To investigate the feasibility of topical psoralen PUVA (sensitization in photosensitizing psoralen drug + UVA radiation) treatment of oral lichenoid lesions (OLL). STUDY DESIGN: A total of 16 patients with OLL were treated using a 0.01% trioxsalen ointment and UVA doses in the 0.09 to 1.80 J/cm2 range. The average number of sessions was 8.7 and a mean cumulative irradiation dose was 4.25 J/cm2. RESULTS: A marked-to-complete healing occurred in 3 to 16 (19%) patients immediately after therapy, in 4 of 14 (29%) after 3 months, and in 5 of 14 (38%) after 14 months, respectively. Of the 16 subjects with OLL, five were diagnosed as oral lichen planus (OLP) and 11 were classified as oral lichenoid reaction (OLR). Post-PUVA amelioration rate in patients with genuine OLP (4 of 5, 80%) was superior to that in patients with OLR (1 of 9, 11%). CONCLUSION: Topical trioxsalen photosensitization can be used in mouth-PUVA treatment, and lichen planus is a main indication for this therapy.

Administration, Topical↗

PubMed1997

Effect of snuff on cytokeratin expression in oral vestibular sulcus epithelium.

Differences in the expression of cytokeratins (CK) in specimens obtained from snuff-affected oral epithelium of the maxillary vestibular sulcus and clinically normal sulcular epithelium were studied by indirect immunofluorescence staining with a panel of monoclonal antibodies (MAbs). CK 14, a marker of stratified squamous epithelium was not seen expressed in 3/11 of the snuff user's specimens. Terminal differentiation markers, typical of cornified epithelia (CK 1, 9, 10 and 11), were detected suprabasally in the snuff user's keratosis but not in the normal control epithelium. The use of snuff seemed to change the CK staining pattern of the mucosa so that it resembles more that of a cornified type of epithelium. Simple epithelial-type CK were included in the study in order to establish the CK profile of the snuff-induced keratosis, for comparison with normal and dysplastic lesions. MAb to CK 7 and 19 showed reactivity in the basal cells and suprabasally whereas the monospecific MAb anti-CK 7 showed suprabasal staining both in the control and affected epithelia. By using MAbs, we found no immunoreactivity against CK 18 either in normal or affected epithelia, whereas we found suprabasal reaction (5/11) against CK 8 in the snuff user's epithelia. The two MAbs demonstrating the expression of CK 19, normally confined to the basal cells of the stratified squamous epithelium, showed variable patterns of expression both in basal cells and suprabasally in the snuff lesions. The results show that use of oral snuff causes some alterations in the CK expression pattern of the affected epithelium. Whether the alterations are indicative of a premalignant change is, however, uncertain. The results encourage further studies on the subject.

Adult↗

PubMed1997

Effect of snuff and smoking on tenascin expression in oral mucosa.

We have shown, by using two monoclonal antibodies (143DB7 and 100EB2), that the expression of the extracellular matrix protein tenascin (Tn) is increased in the connective tissue of biopsies taken from snuff users' and tobacco smokers' oral mucosa. In normal oral mucosa Tn was seen to underlie the epithelium as a thin delicate band. The most increase in Tn reaction was observed in snuff users' mucosa while the immunoreaction in smokers' mucosa was less conspicuous. Often the most prominent Tn reaction took place in association with round cell inflammatory infiltration, indicating epithelial irritation. Tn has been shown to take part in epithelial-mesenchymal interactions during embryogenesis, wound healing and tumorigenesis. Here, a superficial epithelial irritant has been shown to cause conspicuous alterations not only in the epithelial cell layers but also in the underlying connective tissue by increasing its Tn content. As a result of our findings we suggest a further link for Tn in a dynamic epithelial-mesenchymal interplay by virtue of this marked connective tissue reaction in snuff users' and smokers' oral mucosa.

Adult↗

PubMed1997

The activin-binding protein follistatin is expressed in developing murine molar and induces odontoblast-like cell differentiation in vitro.

It has recently been shown that mice deficient in activin-beta A subunits and follistatin exhibit major defects in dentition. To increase understanding of the roles played by these molecules during tooth development, we determined the temporospatial expression of activin-beta A subunit and follistatin messenger RNA and their corresponding proteins in developing murine molars (between day E 14 and 2 days after birth). The effects of recombinant human activin A and its binding protein follistatin on odontoblast differentiation were also studied in cultures of dental papillae (DP) isolated from the mandibular first molars of E-17-day mice. In situ hybridization indicated that transcripts for activin-beta A subunit were abundant in pre-odontoblasts at the tips of forming cusps prior to odontoblast terminal differentiation, and transcripts for follistatin in overlying inner enamel epithelial cells (pre-ameloblasts). Pre-odontoblasts were also weakly immunoreactive in relation to activin-beta A subunit, pre-ameloblasts in relation to follistatin. When follistatin was added at different concentrations to a DP culture model (2-14 nmol/DP) together with heparin at constant concentration, differentiation of odontoblast-like cells was induced, as evidenced by polarization and deposition of extracellular matrix in vitro, to extents depending on the follistatin concentration. In contrast, the addition of activin A (2 nmol/DP) had no effect on the differentiation parameters studied. These findings suggest that the activin-follistatin system regulates odontoblast differentiation during tooth development. In particular, we suggest that binding of endogenous activin A by follistatin may allow odontoblast terminal differentiation to occur.

Activins↗

PubMed1995

Expression of basement membrane type IV collagen and type IV collagenases (MMP-2 and MMP-9) in human fetal teeth.

Formation and degradation of dental basement membrane (BM) are important for tooth development. Data on the expression of genes for type IV collagen (the major structural component of the BM) and type IV collagenases [MMP-2 (72 kDa) and MMP-9 (92 kDa)], enzymes that degrade type IV collagen during human tooth development, are lacking. We studied expression of type IV collagen and the MMP-2 and MMP-9 in human fetal teeth (from the 13th to the 20th gestational weeks, covering cap stage through early hard tissue formation). During cap and bell stages, in situ hybridization located transcripts for alpha 1 type IV collagen chain in the fibroblasts surrounding the enamel organ. No alpha 1 type IV collagen chain mRNA was detected in tooth germ epithelium or dental papilla. However, type IV collagen immunoreactivity was observed in BM underlying the dental epithelium up to the appositional stage. Transcripts for MMP-2 were located mostly in the cells of the dental papilla and follicle. Transient expression of MMP-2 mRNA was observed in the inner enamel epithelium of late cap/early bell-stage teeth. During early apposition, a high level of MMP-2 was confined to secretory odontoblasts. Transcripts for MMP-9 were detected by the sensitive reverse-transcription polymerase chain reaction (RT-PCR) in developing teeth. Thus, in dental BM, alpha 1 type IV collagen chain may be of mesenchymal cell origin. Further, MMP-2 but not MMP-9 may participate in remodeling and degradation of BM during human tooth morphogenesis.

Antisense Elements (Genetics)↗

PubMed1994

Stage-specific expression of decapentaplegic-Vg-related genes 2, 4, and 6 (bone morphogenetic proteins 2, 4, and 6) during human tooth morphogenesis.

Members of the decapentaplegic-Vg-related (DVR) gene family are diffusible signaling molecules regulating inductive tissue interactions during vertebrate development. Expression of DVR/bone morphogenetic protein (BMP) 2, 4, and 6 was studied in human fetal teeth. Sequential morphogenetic stage-specific studies of DVR/BMP 2 and 4 mRNA expression by in situ hybridization revealed transcripts for DVR/BMP 4 during compaction of the dental mesenchyme. In contrast, DVR/BMP 2 mRNA appeared later during tooth development and was located in differentiated cells (odontoblasts). These results were confirmed by reverse-transcription polymerase chain reaction (RT-PCR), which detected DVR/BMP 2 and 4 mRNA in human tooth-germ samples. DVR/BMP 6 protein was distributed in the early dental epithelium and, later, in pre-odontoblasts and odontoblasts, where it remained during dentin formation. These results suggest that DVR/BMP 4 is involved in the early tooth morphogenesis. DVR/BMP 6 may, in particular, be implicated in epithelial-mesenchymal interactions controlling cytodifferentiation. DVR/BMP 2 and 6 may also be involved in odontoblast secretory function. The results suggest that members of the DVR gene family may play regulatory roles during human tooth development.

Base Sequence↗

PubMed1993

Inhibin/activin subunit mRNA expression in human granulosa-luteal cells.

We studied the expression of inhibin/activin subunit mRNAs in granulosa-luteal cells of preovulatory ovarian follicles obtained from women undergoing in vitro fertilization, and in corpus luteum tissue samples of early pregnancy. Northern analysis of granulosa-luteal cell and corpus luteum RNA with single-stranded cDNA or cRNA probes revealed an 1.6-kb mRNA for the alpha subunit and about 6.0-, 4.0-, 2.8-, and 1.7-kb transcripts for the beta A subunit. No clear hybridization signal for the beta B subunit could be detected. The relative expression levels of alpha and beta A subunit mRNAs were determined at 2-day intervals in granulosa-luteal cells cultured for 5 to 11 days. The levels of alpha subunit mRNAs declined steadily with increasing culture age, whereas those of beta A remained unchanged. Reverse transcription-polymerase chain reaction analysis with 35 amplification cycles confirmed the expression of alpha and beta A subunit mRNAs in cultured granulosa-luteal cells. The beta B transcripts were also weakly detectable by this sensitive assay. In situ hybridization of human early pregnancy corpus luteum revealed intense hybridization with the alpha cRNA probe and a weaker signal for the beta A subunit in the granulosa cell compartment. We conclude that: (1) the inhibin alpha and beta A subunits (and to a lesser extent beta B) are expressed in cultured human granulosa-luteal cells; (2) during extended culture periods the alpha/beta A mRNA expression ratio decreases; and that (3) the alpha and beta A subunit mRNA expression is observed in the granulosa cell compartment of early pregnancy corpora lutea.

Activins↗

PubMed1993

Transforming growth factor beta 2 in epithelial differentiation of developing teeth and odontogenic tumors.

Dysregulation of TGF beta 2, a modulator of cell growth and differentiation, can result in uncontrolled growth and tumor formation. Our comparative studies on the expression of TGF beta 2 mRNA and protein indicate that TGF beta 2 may primarily be a regulator of epithelial differentiation during tooth development (between 13 and 20 gestational wk) and tumorigenesis of odontogenic neoplasms. A paracrine mode of action for TGF beta 2 in early human tooth germ (cap/early bell stage) is suggested by location of mRNA in the mesenchyme surrounding the tooth germ, whereas protein is found in the epithelial dental lamina and enamel organ. During the late bell stage, TGF beta 2 gene expression shifted from the mesenchyme to the odontogenic epithelium and was colocalized with protein, suggesting an autocrine role for the terminal differentiation of ameloblasts. In odontogenic tumors of epithelial origin (ameloblastomas) and epithelial-ectomesencymal origin (ameloblastic fibromas), TGF beta 2 mRNA was mostly located in the mesenchymal tumor component and protein in the epithelial tumor component. Odontogenic ectomesenchymal tumors (myxomas) were not associated with TGF beta 2 mRNA and protein expression. The results imply that TGF beta 2 may play an important role in epithelial-mesenchymal interactions in human tooth morphogenesis and development of odontogenic tumors.

Adolescent↗

PubMed1993

EGF receptor and its ligands, EGF and TGF-alpha, in developing and neoplastic human odontogenic tissues.

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) regulate cell proliferation and functional maturation through the EGF receptor (EGF-R). Their roles in human tooth development and odontogenic tumorigenesis have not been explored. We studied the expression of EGF, TGF-alpha and EGF-R in human fetal teeth (cap stage to early hard tissue formation) and various odontogenic tumors. EGF-R mRNA and immunoreactive cells were mostly located in odontogenic epithelium. EGF-R expression was subject to temporospatial variation at different stages of tooth development. EGF and TGF-alpha mRNAs were detected in fetal teeth only by the reverse transcription polymerase chain reaction (RT-PCR). However, EGF and TGF-alpha immunoreactive cells were demonstrated in epithelial elements of tooth germ, suggesting that the peptides partially originate from non-odontogenic sources. In odontogenic tumors, EGF-R mRNA and immunoreactivity were confined to neoplastic epithelium. Transcripts for TGF-alpha but not for EGF were detected in tumors of odontogenic epithelial, epithelial-ectomesenchymal and ectomesenchymal origins. It is concluded that regulation of EGF-R expression is developmentally regulated in human odontogenesis. Furthermore, the odontogenic epithelium is the main target tissue for both EGF and TGF-alpha during tooth development. TGF-alpha and its receptor may also be involved in odontogenic tumorigenesis.

Adolescent↗

PubMed1992

Developmental and cyclic adenosine 3',5'monophosphate-dependent regulation of inhibin subunit messenger ribonucleic acids in human fetal testes.

Inhibin subunit messenger ribonucleic acids (mRNAs) are expressed during the gonadal development of rodent, ovine, and bovine fetuses. We investigated the expression of inhibin subunit mRNAs in human fetal gonads between 13 and 25 weeks of gestational age. In testes, the alpha-subunit mRNA was highly expressed at the beginning of the second trimester and its expression level slightly decreased thereafter. Also the beta B-subunit mRNA was detected throughout this time period but no significant developmental change could be observed. Northern analysis showed a 1.6-kilobase (kb) transcript for alpha-chain, as well as two bands of about 5.0 and 4.5 kb for the beta B-subunit. A human Leydig cell tumor also expressed the 1.6-kb alpha-subunit. By filter hybridization studies, the beta A-chain mRNA could not be observed in testes and none of the three inhibin subunits were detectable in the ovaries at this developmental stage. However, reverse-transcription polymerase chain reaction analysis revealed the expression of all three inhibin subunit mRNAs in testes. As studied by in situ hybridization, inhibin alpha-subunit hybridization signal was most intense in seminiferous tubules and weaker hybridization was observed in interstitial cells of the fetal testis. In primary cultures of fetal testicular cells, dibutyryl cAMP (0.2 mmol/L) stimulated alpha- and beta B-mRNAs. It augmented alpha- and beta B-mRNA accumulation up to 6- and 2.5-fold, respectively. Thus, we conclude that: 1) during the second trimester of gestation, human fetal testes express all three inhibin subunit mRNAs, although the beta A-chain expression appears to be low; 2) during this developmental stage inhibin subunit mRNAs are not detectable in ovaries; 3) in human fetal testes, the alpha-chain mRNA is localized to both intratubular and interstitial cells; 4) in cultured human testicular cells, inhibin alpha- and beta B-subunit mRNAs are regulated by a cAMP-dependent pathway.

Animals↗