Interaction of cells with extracellular matrix (ECM) molecules is necessary for survival of normal cells. In addition, the distinct ECM niche in the cell’s microenvironment is a key regulator of cell differentiation during organogenesis and embryonic development. It is also an important regulator of cell functions during tissue homeostasis, inflammation, wound repair and pathological processes. Interaction of cells with the ECM niche is mostly mediated by integrins that recognize specific signaling sequences in ECM molecules. Integrins convey this information into cells and induce signaling cascades that regulate gene expression and cell functions. These signaling pathways collaborate with signals from growth factor receptors. The major interest in the laboratory is to understand the mechanisms by which integrins and extracellular matrix molecules in the cellular microenvironment (niche) modulate cell adhesion, migration, growth and gene expression during wound healing and scar formation in skin and oral mucosa. Furthermore, we also study the role of cell-ECM interactions in the development, homeostasis and pathological conditions in the oral mucosal, dental and periodontal tissues. For these purposes, our laboratory has developed novel animal, cell and organotypic culture models, and uses some of the latest techniques in cell and molecular biology, histology and microscopy.
Tammi R, Tammi M, Häkkinen L,
Larjava H. Histochemical
localization of hyaluronate in human oral epithelium using a specific
hyaluronate-binding probe. Arch Oral Biol, 35:219-224, 1990.
Larjava H, Häkkinen L,
Rahemtulla F. A
biochemical analysis of human periodontal tissue proteoglycans.
Biochem J, 284, 267-274, 1992.
Häkkinen L, Larjava H.
Characterization
of fibroblast clones from periodontal granulation tissue in vitro.
J Dent Res, 71, 1901-1907, 1992.
Häkkinen L, Oksala O, Salo T, Rahemtulla F, Larjava
H. Immunohistochemical
localization of proteoglycans in human periodontium. J Histochem
Cytochem, 41, 1689-1699, 1993.
Häkkinen L, Heino J, Koivisto
L, Larjava H. Altered
interaction of granulation tissue fibroblasts with fibronectin
is regulated by a5β1 integrin. Biochim Biophys Acta (Molecular
Cell Research), 1224, 33-42, 1994.
Koivisto L, Heino J, Häkkinen
L, Larjava H. The
size of the intracellular beta 1-integrin precursor pool regulates
maturation of beta 1-integrin subunit and associated alpha-subunits.
Biochem J, 300, 771-779, 1994.
Oksala O, Salo T, Tammi R, Häkkinen
L, Jalkanen M, Inki P, Larjava H. Expression
of proteoglycans and hyaluronan during wound healing. J Histochem
Cytochem, 43, 125-135, 1995.
Kähäri V-M, Häkkinen
L, Westermarck J, Larjava H. Differential
regulation of decorin and biglycan gene expression by dexamethasone
and retinoic acid in cultured human skin fibroblasts. J Invest
Dermatol, 104, 503-508, 1995.
Westermack J, Häkkinen L,
Fries W, Kähäri V-M. TNF-R55-specific
form of human tumor necrosis factor-a induces collagenase gene
expression by human skin fibroblasts. J Invest Dermatol, 105,
197-202, 1995.
Häkkinen L, Westermarck
J, Kähäri V-M, Larjava H. Human
granulation-tissue fibroblasts show enhanced proteoglycan expression
and an altered response to TGF-β1. J Dent Res, 75, 1767-1778,
1996.
Oksala O, Haapasalmi K, Häkkinen L, Uitto V-J, Larjava
H. Expression
of heparan sulphate and small dermatan/chondroitin sulphate proteoglycans
in chronically inflamed human periodontium. J Dent Res, 76,
1250-1259, 1997.
Johansson N, Westermarck J, Leppä S, Häkkinen
L, Koivisto L, Lopez-Otin C, Peltonen J, Heino J, Kähäri
V-M. Collagenase-3
(matrix metalloproteinase 13) gene expression by HaCaT keratinocytes
is enhanced by tumor necrosis factor-α and transforming growth
factor-β1. Cell Growth Differ, 8, 243-250, 1997.
Soukka T, Salmi M, Joensuu H, Häkkinen L, Sointu
P, Koulu L, Kalimo K, Klemi P, Grenman R, Jalkanen S. Malignant
transformation in squamocellular cancer is associated with down
regulation of CD44v6. Cancer Res, 57, 2281-2289, 1997.
Kainulainen T, Häkkinen L,
Hamidi S, Larjava K, Kallioinen M, Peltonen JM, Salo T, Larjava
H, Oikarinen A. Essential
role for laminin-5 during reepithelialization of wounds. J
Histochem Cytochem, 46:353-360, 1998.
Häkkinen L, Westermarck
J, Johansson N, Aho H, Peltonen J, Heino J, Kähäri V-M.
Suprabasal
expression of epidermal α2β1 and α3β1 integrins in skin treated
with topical retinoic acid. Br J Dermatol, 138:29-36, 1998.
Reunanen N, Westermarck J, Häkkinen
L, Holmström T, Elo I, Eriksson J, Kähäri
V-M. Enhancement
of fibroblast collagenase (MMP-1) gene expression by ceramide
is mediated by extracellular stimulus-regulated and stress-activated
protein kinase pathways. J Biol Chem, 273:5173-5145, 1998.
Häkkinen L, Kainulainen
T, Salo T, Sheppard D, Larjava H. Expression
of integrin α9 subunit and tenascin in oral leukoplakia, lichen
planus, and squamous cell carcinoma. Oral Diseases, 5:210-217,
1999.
Koivisto L, Larjava K, Häkkinen
L, Uitto V-J, Heino J, Larjava H. Different
integrins mediate cell spreading, haptotaxis and lateral migration
of HaCaT keratinocytes on fibronectin. Cell Adhes Commun,
7:245-257, 1999.
Ravanti L, Häkkinen L,
Larjava H, Saarialho-Kere U, Fischi M, Han J, Kähäri
V-M. Transforming
growth factor-β induces collagenase-3 expression by human gingival
fibroblasts via p38 mitogen-activated protein kinase. J Biol
Chem, 274:37292-37300, 1999.
Häkkinen L, Hildenbrand HC, Berndt A, Kosmehl H,
Larjava H. Immunolocalization
of tenascin-C, α9 integrin subunit and αvβ6 integrin during wound
healing in human oral mucosa. J Histochem Cytochem, 48:985-998,
2000.
Rechardt O, Elomaa O, Vaalamo M, Pääkkönen K,
Jahkola T, Höök-Nikanne J,Hembry RM, Häkkinen
L, Kere J, Saarialho-Kere U. Stromelysin-2
(MMP-10) is upregulated during normal wound repair and is induced
by cytokines. J Invest Dermatol, 115:778-787, 2000.
Häkkinen L, Strassburger
S, Scott P, Kähäri V-M, Eichstetter I, Iozzo RV, Larjava
H. A
role for decorin in the structural organization of periodontal
ligament. Lab Invest, Invest, 80:1869-80, 2000.
Hildebrand HC, Häkkinen L, Wiebe C, Larjava H. Characterization
of organotypic keratinocyte cultures on de-epithelialized tongue
mucosa. Histology & Histopathology, 17:151-163, 2002.
Ghersi G, Dong H., Goldstein LA, Yeh Y, Häkkinen
L, Larjava HS, Chen W-T. Regulation
of fibroblast migration on collagenous matrix by a cell surface
peptidase complex. J Biol Chem, 277:29231-29241, 2002.
Häkkinen L, Koivisto L,
Larjava H. An improved method for culture of epidermal keratinocytes
from newborn mouse skin. Methods in Cell Science, 23:189-196,
2002.
Leivonen S-K, Chantry A, Häkkinen
L, Han J, Kähäri V-M. Smad3
mediates transforming growth factor-β-induced collagenase-3 (MMP-13)
expression in human gingival fibroblasts. Evidence for cross-talk
between Smad3 and p38 signaling pathways. J Biol Chem, 277:46338-46346,
2002.
Wiebe CB, Penagos H, Luong N, Slots J, Epstein E Jr, Siegel D,
Häkkinen L, Putnins EP, Larjava HS. Clinical
and microbiologic study of periodontitis associated with kindler
Syndrome. J Periodontol, 74:25-31, 2003.
Koivisto L, Alavian K, Häkkinen L, McCulloch CA,
Larjava H. Glycogen
synthase kinase-3 regulates extended lamellipodia formation in
human keratinocytes. J Cell Science, 116:3749-3760, 2003.
Impola U, Uitto V-J, Hietanen J, Häkkinen L, Zhang
L , Larjava H, and Saarialho-Kere U. Differential
expression of matrilysin-1 (MMP-7), 92 kDa gelatinase (MMP-9)
and metalloelastase (MMP-12) in oral verrucous and squamous cell
cancer. J. Pathol, 202:14-22, 2004.
Häkkinen L, Koivisto L, Gardner H, Saarialho-Kere,
U, Carroll J, Lakso M, Heino J, Larjava, H. Increased
expression of beta-6 integrin in skin leads to spontaneous development
of chronic wounds. Am J Pathol, 164:229-242, 2004.
Koivisto L, Häkkinen L, Matsumoto K, McCulloch CA,
Yamada K, Larjava H. Glycogen
synthase kinase-3 regulates cytoskeleton and translocation of
Rac1 in long cellular extensions in human keratinocytes. Exp
Cell Res, 293:68-80, 2004.
Jokinen J, Dadu E, Nykvist P, Käpylä J, White DJ,
Ivaska J, Vehviläinen
P, Reunanen H, Larjava H, Häkkinen L, Heino J. Integrin-mediated
cell adhesion to type 1 collagen fibrils. J Biol Chem, 279:31956-31963, 2004.
Alimohamad H, Habijanac T, Larjava H, Häkkinen L. Colocalization
of the collagen-binding proteoglycans decorin, biglycan, fibromodulin, and lumican
with
different cells in human gingiva. J Periodont Res, 40:73-86, 2005.
Matheson S, Larjava H, Häkkinen L. Distinctive
localization and function for lumican, fibromodulin and decorin
to regulate
collagen fibril organization in periodontal tissues. J Periodont
Res, 40:312-324, 2005.
Leivonen S-K, Häkkinen L, Liu D, Kähäri
V-M. Smad3
and extracellular signal-regulated kinase 1/2 coordinately mediate
transforming growth factor-ß-induced expression of connective
tissue growth factor in human fibroblasts. J Invest Dermatol,
124:1162-1169, 2005.
Bhide VM, Laschinger CA, Arora PD, Lee W, Häkkinen
L, Larjava H, Sodek J, McCulloch CAG. Collagen
phagocytosis by fibroblasts is regulated by decorin. J
Biol Chem, 280:23103-23113, 2005.
Aldahlawi S, Eslami A, Häkkinen L, Larjava H. The avb6 integrin plays a role in compromised epidermal wound healing. Wound Repair Regen 14:289-297, 2006.
Honardoust D, Jiang G, Koivisto L, Wienke D, Isacke C, Larjava H, Häkkinen L. Expression of Endo180 is spatially and temporally regulated in distinct cells during wound healing. Histopathology 49:634-648, 2006.
Koivisto L, Jiang G, Häkkinen L, Chan B, Larjava H. HaCaT keratinocyte migration is dependent on epidermal growth factor receptor signaling and glycogen synthase kinase-3alpha. Exp Cell Res 15:2791-2805, 2006.
Walsh P, Häkkinen L, Pernu H, Larjava H. Integrin expression in drug-induced gingival overgrowth. J Periodontal Res 42:144-151, 2007.
Csiszar A, Wiebe C, Larjava H, Häkkinen L. Distinct molecular composition of human interdental papilla. J Periodontol, 78:304-314, 2007.
Narani N, Owen GRh, Häkkinen L, Putnins E, Larjava H. Enamel matrix proteins bind to wound provisional matrix proteins and regulate their cell adhesive properties. Eur J Oral Sci. 115:288-95, 2007.
Wiebe CB, Petricca G, Häkkinen L, Jiang G, Wu C, Larjava HS. Kindler syndrome and periodontal disease: Review of the literature and 12-year follow-up of treatment outcome. J Periodontol, 79:961-966, 2008.
Ghannad F, Nica D, Garcia MI, Grenier D, Johnston S, Eslami A, Koivisto L, Putnins EE, Jiang G, McKee MD, Häkkinen L, Larjava H. Absence of avb6 integrin is linked to initiation and progression of periodontal disease. Am J Pathol, 172:1271-1286, 2008.
Honardoust D, Eslami A, Larjava H, Häkkinen L. Localization of Small Leucine-Rich Proteoglycans and Transforming Growth Factor-b in human oral mucosal wound healing. Wound Repair Regen, 16:814-823, 2008.
Eslami A, Gallant-Behm C, Hart D, Wiebe C, Honardoust D, Gardner H, Häkkinen L, Larjava HS. Expression of Integrin avb6 and TGF-b in Scar-free vs. Scar-forming Wound Healing. J Histochem Cytochem, 57:543-557, 2009.
Xie Y, Gao K, Häkkinen L, Larjava H. Loss of b6 integrin partially ameliorates dexamethasone-impaired cutaneous wound healing. Wound Repair Regen, 17:326-329, 2009.
Petricca G, Leppilampi M, Jiang G, Owen GRh, Wiebe C, Tu Y, Koivisto L, Häkkinen L, Wu C, Larjava H. Kindlin-1 interacts with migfilin and supports keratinocyte adhesion, proliferation and migration. Eur J Oral Sci, 117:516-527, 2009.
Wong JW, Gallant-Behm C, Wiebe C, Mak K, Hart DA, Larjava H, Häkkinen L. Wound healing in oral mucosa results in reduced scar formation as compared to skin: Evidence from the red Duroc pig model and humans. Wound Repair Regen, 17:717-729, 2009.
Mak K, Manji A, Gallant-Behm CL, Wiebe C, Hart DA, Larjava H, Häkkinen L. Scarless healing of oral mucosa is characterized by faster resolution of inflammation and control of myofibroblast action compared to skin wounds in the red Duroc pig model. J Dermatol Sci, 56:168-180, 2009.
Owen GRh, Häkkinen L, Wu C, Larjava H. Labeling antigens using preformed fluorescent molecular IgG-F(ab’)2 complexes from primary antibodies of the same species. Microsc Res Techniq, in press, 2009.
