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t-PA was being measured in the bovine endothelial cells. Also, in the endothelial cells, IL-1 and TGFI3 lowered net PA activity (23). The appearance of the rheumatoid synovium has been likened to the appearance of a tumor with synovial fibroblast-like cells proliferating and adopting a "transformed" appearance possibly due to cytokine action (24, 25). In the early phase of cartilage destruction in rheumatoid joints by the active cellular "pannus" or granulation tissue, cartilage is covered by several layers of fibroblast-like cells, even at the advancing edge, the other predominant cell being the macrophage (24-26). These findings have led to the proposal that, while immune cells play an important role in the pathologic process, proliferating cells of mesenchymal connective tissue origin also appear to be significant in directly mediating bone and cartilage resorption (24-26). These in vivo observations are supported by in vitro ones showing that rheumatoid synovial cells form colonies in agar (7, 27) and secrete PA

activity (27). We have suggested before that the enhanced PA activity in these cells, as a result of the influence of monocyte-macrophage cytokines, could be reflecting the expression of an immature, invasive, "tumor-like" phenotype, which is consistent with the morphologic and functional descriptions of the "pannus" (6, 17). Given that IL-1 and TGF~ have been found in rheumatoid synovial fluids (28, 29) and that both can cause arthritis in animal models (30, 31), it would be intriguing to know whether oncostatin M is also present in rheumatoid joints and whether it may play a role in the pathogenesis of this disease, perhaps by causing a phenotypic change in the synovial lining cells as described. ACKNOWLEDGMENTS

The authors wish to thank P. Linsley and S. Radka, Bristol-Myers Squibb Pharmaceutical Research Institute, for the supply of oncostatin M and its rabbit antiserum, respectively; Ms. S. Wong and Mr. D. Finn are thanked for typing the manuscript.

ILREKRK/~7,K~ 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Malik, N., Kallestad, J.C., Gunderson, W.L., Austin, S.D., Neubauer, M.G., Ochs, V., Marquardt, H., Zarling, J.M., Shoyab, M., Wei, C., Linsley, P.S. and Rose, T.M. (1989) Mol. Cell Biol. 9. 2847-2853. Zarling, J.M., Shoyab, M., Marquardt, H., Hanson, M.B., Lioubin, M.N. and Todaro, G.J. (1986) Prec. Natl. Acad. Sci. USA 83. 9739-9743. Brown, T.J., Uoubin, M.N. and Marquardt, H. (1987) J. Immunol. 139. 2977-2983. Linsley, P.S., Hanson, M.B., Horn, D., Malik, N., Kallestad, J.C., Ochs, V., Zarting, J.L. and Shoyab, M. (1989) J. Biol. Chem. 264. 4282-4289. Horn, D., Fitzpatrick, W.C., Gompper, P.T., Ochs, V., Bolton-Hansen, M., Zading, J.L, Malik, N., Todaro, G.J. and Linsley, P.S. (1990) Growth Factors 2. 157-165. Hamilton, J.A. (1983) J. Rheumatol. 10. 845-851. Lafyatis, R., Remmers, E.F., Roberts, A.B., Yocum, D.E., Sporn, M.B. and Wilder, R.L. (1989) J. Clin. Invest. 83. 1267-1276. Leizer, T., Clards, B.J., Ash, P.E., van Damme, J., Saklatvala, J. and Hamilton, J.A. (1987) Arthritis Rheum. 30. 562-566. Dayer, J.-M., de Rochemonteix, B., Burrus, B., Demczuk, S. and Dinarello, C.A. (1986) J. Clin. Invest. 77. 645-648. Butler, D.M., Vitti, G.F., Leizer, T, and Hamilton, J.A. (1988) Arthritis Rheum. 31. 1281-1289. Guerne, P.A., Zuraw, B.L., Vaughan, J.H. and Lotz, M. (1989) J. Clin. Invest. 83. 585-592. Butler, D.M., Piccoli, D.S., Hart, P.H. and Hamilton, J.A. (1988) J. Rheumatol. 15. 1463-1470. Dane, K., Andreasen, P., GrondahI-Hansen, J., Kdstensen, P., Nielsen, L. and Skriver, L. (1985) Adv. Cancer Res. 44. 139-266. Werb, Z., Mainardi, C.L., Vater, C.A. and Harris, E.D.J. (1977) New Engl. J. Med. 296. 10171023. Mochan, E. and Uhl, J. (1984) J. Rheumatol. 11. 123-128. Lack, C.J. and Rogers, H.J. (1958) Nature 182. 948. Hamilton, J.A. and Slywka, J. (1981) J. Immunol. 126. 851-855. Vitti, G. and Hamilton, J.A. (1988) Arthritis Rheum. 21. 1046-1051.

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stimulation of synoviocyte DNA synthesis by IL-1 arid TNFc~ (12), we determined whether the addition of a cyclooxygenase inhibitor, indomethacin, could influence the action of oncostatin as a stimulator of DNA synthesis. As presented in Table Ill, indomethacin could potentiate its action in this cell line; likewise, as reported previously (12), indomethacin gave a similar result with IL-I(x. In Table Ill, we show that oncostatin M did not inhibit the stimulation of DNA synthesis by IL-I(~ in the presence of indomethacin. When the DNA synthetic responses of two other synovial cell lines were examined in the presence of oncostatin M and indomethacin, oncostatin M (> 0.2 U/ml) again had a weak effect which was enhanced by indomethacin in one of the lines but not in the other. However, in three other lines, this cytokine could not stimulate DNA synthesis under the same culture conditions irrespeclive of whether indomethacin was present in the cultures; in these last experiments, IL-I(x was active, particularly in the presence of indomethacin.

DISCUSSION We have shown here that oncostatin M (> 0.2 U/ml = lpM) can stimulate rapidly the u-PA activity and mRNA expression in human synovial fibroblast-like cells. These findings indicate that synoviocytes can be added to the list o! cells, which respond to oncostatin M, presumably via cell surface receptors (4); they also indicate that oncostatin M joins the cytokines, which have been shown to raise u-PA activity and mRNA expression in these cells, viz. IL-1 (8, 18) and TGFI3 (21). As for IL-1 (8), oncostatin M also stimulated PGE2 production by the synoviocytes but the amount of PGE2 produced was much lower than for IL-1 (Table II); in contrast, we have evidence that TGFI3 does not alter PGE2 synthesis (21). Again, as for IL-1 and TGFI~, oncostatin M stimulated DNA synthesis, but, unlike the other cytokines, its activity was inconsistent for unexplained reasons - this inconsistency has also been reported in the same action of interferon 7 (12). As has been shown for the effects of IL-1 and TNF(~ on the synovial fibroblast DNA synthesis, the degree of stimulation could be enhanced sometimes by inclusion of a cyclooxygenase inhibitor, such as indomethacin, in the cultures (12) - evidence was provided before that exogenous PGE2 could reverse the effect of indomethacin and that sufficient PGE2 could be produced in the cytokine-treated cultures to lower the level of DNA synthesis (12). Presumably, in some of the oncostatin-treated cultures there was sufficient endogenous cyclooxygenase product, such as PGE2, to have a modulatory effect on DNA synthesis. Oncostatin M was originally described by its ability to inhibit the growth of tumor cells (2); however, its effect on our synoviocytes seems similar to that published on other human fibroblast cell lines where there was augmentation of cell proliferation (2, 5). In summary, there are some similarities but also some differences in the effects of IL-1, TGFI3 and oncostatin M on the human synoviocytes(9-11). It is interesting that others have shown that oncostatin M and TGFI3 act synergistically to inhibit the growth of melanoma cells (3) but act antagonistically on mesenchymal fibroblast proliferation (22). Using the same oncostatin M, it has been reported that it can raise an uncharacterized PA activity of bovine aortic endothelial cells (23); however, concentrations > ~ 100 pM were required, these concentrations being approximately 20 times more than that needed to inhibit proliferation of the same cells. Our findings with the stimulation of human synoviocyte u-PA activity and DNA synthesis occurring at similar concentrations seem to differ from this report although it is possible that

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TABLE I. Effects of TGF-I~ o n type VII a n d type I collagen, flbronectin, a n d GAPDH g e n e e x p r e s s i o n in h u m a n e p i d e r m a l k e r a t i n o e y t e (HEK) a n d h u m a n s k i n f i b r o b l a s t (HSF) cultures a Cell C u l t u r e

~t 1 (VII)

HEK, control HEK + TGF-131 HEK + TGF-I~2 HSF, c o n t r o l HSF + TGF-132

1.4 (I.0} 7.415.3) 8,8 (6.3) 0.5 (1.0) 3.1 (6.2}

m R N A A b u n d a n c e [U/try) et 11I) FN hiD b ND ND 1,9 (1.01 3.2 (1.7)

0.9 {I.0} 40.1 (45.61 31.6 (35.1) 1.4 (1.0} 7,8 (5.6)

GAPDH 5.1 (1.0} 5.411.1} 4.6 (0.9) 6.2 (1.01 6.6 (I. I)

a The cell c u l t u r e s were i n c u b a t e d with TGF-131 or TGF-132 (I n g / m l ) a n d mRNA a b u n d a n c e w a s q u a n t i t a t e d b y s c a n n i n g d e n s i t o m e t r y of t h e N o r t h e r n b l o t s s h o w n In Fig. 1. T h e v a l u e s are e x p r e s s e d a s relative d e n s i t o m e t r i c u n i t s (U) p e r lag RNA analyzed. T h e v a l u e s in p a r e n t h e s i s indicate fold i n d u c t i o n in relation to respective control c u l t u r e s i n c u b a t e d w i t h o u t TGF-IL b ND, no mRNA detected.

(Table I). Interestingly, t h e a l(Vll) c o l l a g e n m R N A in s k i n f i b r o b l a s t c u l t u r e s i n c u b a t e d with TGF-~2 a p p e a r e d to c o n s i s t of two closely migrating b a n d s (Fig. 1). The r e a s o n for the two different sizes of mRNAs is n o t clear at this point, b u t could reflect either alternative splicing of type VII collagen p r e - m R N A s (27), or c o u l d r e s u l t from d i f f e r e n t i a l u t i l i z a t i o n of t h e p o l y a d e n y l a t i o n signal at the 3'-end of the gene, in a similar m a n n e r as h a s b e e n d e m o n s t r a t e d in case of the ul(1) collagen gene (28). The Northern filter containing RNA from h u m a n skin flbroblasts w a s also r e - h y b r i d i z e d w i t h cDNAs recognizing e i t h e r h u m a n f i b r o n e c t i n or u l(I) collagen s e q u e n c e s . The s t e a d y - s t a t e levels of b o t h f i b r o n e c t i n a n d a 1(I) c o l l a g e n mRNAs w e r e e n h a n c e d b y TGF-~2, i n d i c a t i n g t h a t t h e s e cells r e s p o n d to TGF-~2 in a similar m a n n e r as h a s b e e n p r e v i o u s l y n o t e d with TGF-131 (8). R e - h y b r i d i z a t i o n of t h e N o r t h e r n filter c o n t a i n i n g RNA from h u m a n k e r a t i n o c y t e s with t h e a 1(I) collagen cDNA did n o t yield a d e t e c t a b l e signal (Fig. 1) , This o b s e r v a t i o n is c o n s i s t e n t with p r e v i o u s d e m o n s t r a t i o n s t h a t h u m a n k e r a t i n o c y t e s do n o t s y n t h e s i z e type I collagen (29), a n d it also i n d i c a t e s t h a t t h e k e r a t i n o c y t e c u l t u r e s utilized in o u r s t u d y w e r e n o t c o n t a m i n a t e d b y fibroblastic cells. To illustrate t h a t the elevated type VII collagen mRNA levels detected b y N o r t h e r n a n a l y s e s in fact r e s u l t e d in e n h a n c e d b i o s y n t h e s i s of t y p e VII collagen, indirect immunofluorescence with a monoclonal antibody r e c o g n i z i n g t y p e VII c o l l a g e n e p i t o p e s w a s p e r f o r m e d . In c o n t r o l k e r a t i n o c y t e c u l t u r e s , a relatively faint, y e t clearly d e t e c t a b l e , c y t o p l a s m i c i m m u n o s i g n a l w a s n o t e d (Fig. 2F). I n c u b a t i o n of cells w i t h TGF-131 in c o n c e n t r a t i o n s of 0.5, 1 or 5 n g / m l e n h a n c e d t h e i m m u n o s t a i n i n g w i t h o u t an apparent change in cell m o r p h o l o g y (Fig. 2, G-I). The i m m u n o f l u o r e s c e n c e s t a i n i n g w a s even f u r t h e r e n h a n c e d b y i n c u b a t i o n of 676

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HEK i

i

Probe

HSF r--i

al (VII)

FN

ctl(I) GAPDH TGF-B1

-

+ -

TGF-[32

--

--

-I-

-

-

--

4-

Flaure I. Demonstration that TGF-[31 and TGF-[~2 enhance type VII collagen gene expression in human epidermal keratinocytes (HEK) and human skin flbroblasts (HSF) in culture. The ceils were incubated with TGF-~I or TGF-~2 (1 ng/mll for 29 hrs and Northern analyses were performed with poly(A)+RNA (6 Ixg/lane), as indicated in Methods. Hybridizations with a human alWII) collagen eDNA revealed a band of -8.5 kb, consistent with the size of human type VII collagen mRNA. Re-hybridizations of the same filter with human fibronectin (FN) and al(I) collagen cDNAs revealed the characteristic RNA transcripts of 8 kb, or 5.8 and 4.8 kb, respectively. Incubation of cells with TGF-~I or TGF-J~2 enhanced type VII collagen and flbronectin gene expression in HEK cultures. In addition, the al(I) collagen mRNA levels were increased in human skin flbroblasts, while no type I collagen mRNAs could be detected in HEK cultures, indicating that the HEK cultures were not contaminated with fibmblastic ceils. Rehybridization of the filters with a GAPDH cDNA revealed only small differences in the corresponding mRNA, indicating relatively even loading of RNA to different Northern lanes (see Table I).

(I n g / m l ) .

N o r t h e r n a n a l y s i s of RNA r e v e a l e d a c l e a r l y d e t e c t a b l e b a n d in

RNA i s o l a t e d f r o m c o n t r o l c u l t u r e s , w i t h t h e c h a r a c t e r i s t i c size of (14), w h e n h y b r i d i z e d w i t h a h u m a n

-8.5 kb

t y p e VII c o l l a g e n cDNA (Fig. 1).

The

s i g n a l w a s m a r k e d l y e n h a n c e d in RNA p r e p a r a t i o n s i s o l a t e d f r o m c u l t u r e s i n c u b a t e d e i t h e r w i t h TGF-[~ 1 or TGF-[~2, (Fig. 1). S c a n n i n g d e n s i t o m e t r y o f t h e a u t o r a d i o g r a p h i c b a n d s r e v e a l e d t h a t TGF-[~I a n d TGF-[32 i n c r e a s e d t h e ~ I W I I ) c o l l a g e n m R N A levels b y - 5 . 3 - 6 . 9

fold o v e r t h e c o n t r o l s (Table 1).

R e - h y b r i d i z a t i o n of t h e s a m e filter w i t h a f i b r o n e c t i n cDNA i n d i c a t e d t h a t , in a c c o r d a n c e w i t h p r e v i o u s r e p o r t s (2,3,6), f i b r o n e c t i n m R N A l e v e l s w e r e i n c r e a s e d u p to - 4 5 fold b y TGF-J31 a n d TGF-I$2 (Table I). R e - h y b r i d i z a t i o n of t h e s a m e filter w i t h t h e G A P D H cDNA r e v e a l e d m i n o r d i f f e r e n c e s i n t h e c o r r e s p o n d i n g m R N A levels, i n d i c a t i n g r e l a t i v e l y e v e n l o a d i n g o f RNA. In p a r a l l e l w i t h k e r a t i n o c y t e c u l t u r e s , s k i n f i b r o b l a s t s , w h i c h h a v e b e e n p r e v i o u s l y s h o w n to b e r e s p o n s i v e to TGF-[31 (8), w e r e a l s o i n c u b a t e d w i t h T G F - [ 3 2 (1 n g / m l ) .

Northern analysis with the

~I(VII)

collagen

cDNA

r e v e a l e d a r e l a t i v e l y w e a k s i g n a l in t h e c o n t r o l c u l t u r e s , i n d i c a t i n g low level of e x p r e s s i o n (Fig. 1). T h e i n t e n s i t y of t h i s s i g n a l w a s s i g n i f i c a n t l y e n h a n c e d in c u l t u r e s i n c u b a t e d w i t h TGF-[32 (Fig. 1), a n d s c a n n i n g d e n s i t o m e t r y indicated that the enhancement

w a s u p to 6 . 2 fold o v e r t h e c o n t r o l cells 675

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cells with 10 n g / m l of TGF-[~I, but this was accompanied by a change in the morphology of the individual cells which appeared flattened with enlarged area of cytoplasm (Fig. 2, J). The growth stage and differentiation of normal h u m a n keratinocytes has been shown to be modulated by the calcium concentration in the culture medium, with arrest of cell growth and initiation of differentiation processes taking place at high (1.2 mM) calcium c o n c e n t r a t i o n (17). Subsequently, normal keratinocytes were incubated for 48 hr with or without 5 n g / m l of TGF-~I in m e d i u m c o n t a i n i n g e i t h e r 0.15 or 1.2 mM Ca 2+. I m m u n o f l u o r e s c e n c e i n d i c a t e d t h a t TGF-~I was able to i n c r e a s e the intensity of the immunosignal in both types of cultures (Fig. 3). However, the e n h a n c e m e n t was somewhat more pronounced in cultures maintained in high (1.2 mM) calcium containing medium, suggesting t h a t the cells in stationary phase, as induced by elevated calcium levels, are more responsive to TGF-[~ with r e s p e c t to e n h a n c e d s y n t h e s i s of e x t r a c e l l u l a r m a t r i x components, such as type VII collagen. H u m a n epidermoid carcinoma KB cells have been previously shown to synthesize type VII collagen (30), and we have recently d e m o n s t r a t e d a relatively high a b u n d a n c e of type VII collagen mRNAs in the KB cell cultures (31). Indirect i m m u n o f l u o r e s c e n c e of KB cell cultures indicated t h a t TGF[~I in concentrations varying from 0.5 to 10 ng/ml, markedly e n h a n c e d the immunosignal detected with the monoclonal anti-type VII collagen antibody (Fig. 2). The t r a n s f o r m e d epidermoid cells appeared, therefore, to be equally responsive to TGF-~I as were their normal counterparts.

C F ~ u r e 3. E n h a n c e d type VII collagen expression by TGF-[~I (5 ng/ml) in keratinocyte cultures i n c u b a t e d either in low (0.15 raM) (A,B) or in high (1.2 mM) (C,D) calcium medium. The incubation and staining conditions were the same as in Figure 2. Original magnification was the same in all pictures: bar, 100 pan.

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Figure 2. Indirect immunofluorescence of KB ceil (A-E) and h u m a n epidermal keratinocyte (FJ) cultures incubated with 0 (A,F), 0.5 (B,G), 1.0 (C,H], 5.0 (D-I) or I0.0 (E,J) ng/rnl of TGF-~I for 48 hrs. The c u l t u r e s were stained with a monoclonal antibody L3D recognizing type VII collagen epitopes. A s s e s s m e n t of the i m m u n o s i g n a l indicates e n h a n c e m e n t of type VII collagen epitopes in both cell types. Also note that high concentration (10 ng/ml) of TGF-~ alters the morphology of individual keratinocytes (J). The c u l t u r e s s h o w n in A-E were examined in parallel in one experiment, while those shown in F - J were stained in parallel in another experiment. The photographic exposure time was the same for all cultures, and the prints were reproduced u n d e r identical conditions. Original magnification is the same in all pictures: bar, 100 lam. 677

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T h e r e s u l t s of t hi s s t u d y d e m o n s t r a t e t h a t TGF-~ u p - r e g u l a t e s t y p e VII collagen g e n e e x p r e s s i o n in e p i d e r m a l k e r a t i n o c y t e s a n d in t r a n s f o r m e d KB cells, as d e t e c t e d a t t h e mRNA a n d p r o t e i n levels, T h e u p - r e g u l a t i o n w a s of t h e s a m e m a g n i t u d e b o t h w i t h TGF-~ i a n d TGF-~2, f u r t h e r s u g g e s t i n g t h a t t h e s e two m e m b e r s of TGF-~ family h a v e s i m i l a r biological activities,

The

p r e c i s e m e c h a n i s m s b y w h i c h TGF-~ elicited t h e u p - r e g u l a t i o n of t ype VII c o l l a g e n g e n e e x p r e s s i o n ar e n o t clear.

Previously, type I collagen gene

e x p r e s s i o n h a s b e e n s h o w n to b e m o d u l a t e d b y T G F - ~ I in h u m a n

skin

f i b r o b l a s t c u l t u r e s p r i m a r i l y t h r o u g h e n h a n c e d t r a n s c r i p t i o n a l activity, as detected by transient

transfections with promoter/reporter

g e n e (CAT)

c o n s t r u c t s (8). T h e p r e c i s e c i s - e l e m e n t in t y p e I c o l l a g e n p r o m o t e r r e s p o n s i v e to TGF-~ h a s b e e n s u g g e s t e d to b e t h e NF-1 b i n d i n g site (7), b u t r e c e n t e v i d e n c e al s o s u g g e s t s

a role for AP-1 b i n d i n g s i t e s for TGF-~

r e s p o n s e in o t h e r h u m a n g e n e s , i n c l u d i n g t h e e l a s t i n p r o m o t e r (32). In a d d i t i o n , T G F - ~ I h a s b e e n s h o w n to i n c r e a s e t h e stability of t y p e I collagen mRNAs (33), T h e m e c h a n i s m of collagen mRNA st abi l i zat i on b y TGF-~ is n o t k n o w n , b u t t h e 3' u n t r a n s l a t e d region of mRNAs a p p e a r s to c o n f e r st abi l i t y to s e v e r a l t r a n s c r i p t s of d i v e r s e origin (34).

I r r e s p e c t i v e of t h e p r e c i s e

m e c h a n i s m , t h e e l e v a t e d mRNA levels w e r e s h o w n to l e a d to e n h a n c e d s y n t h e s i s of t y p e VII collagen in t h e p r e s e n c e of T G F-~I. T h u s , TGF-~ m a y e v e n t u a l l y p r o v i d e a p h a r m a c o l o g i c m e a n s to e n h a n c e t y p e VII c o l l a g e n s y n t h e s i s in s i t u a t i o n s in w h i c h a n c h o r i n g fibril f o r m a t i o n h a s b e e n s h o w n to b e slow o r a b s e n t , s u c h as in c u t a n e o u s b u r n s

(35) or in p a t i e n t s w i t h

d y s t r o p h i c e p i d e r m o l y s i s b u l l o s a (36). ACKNOWLEDGMENTS We wish to thank Process Biochemistry Group of Celtrix Laboratories for providing purified TGF-~. Eileen O'Shaughnessy provided excellent secretarial help. This study was supported by USPHS, NIH grants PO1 AR38923 and T32 AR7561, and by the Dermatology Foundation. Dr. Sollberg was supported by the "Deutsche Forschungsgemeinschaft" (So 239/I-1). REFERENCES io 2. 3.

4. 5. 6. 7. 8. 9. I0.

Spom, M.B., and Roberts, A.B. (1988) Nature (Lond)332, 212-219. Roberts, A.B., Heine, U.I., Flanders, K.C., and Sporn, M.B. (1990) Ann. N.Y. Acad. Sci. 580, 225-232. Ignotz, R.A., and Massague, J. (1986) J. Biol. Chem. 261, 4337-4345. Varga, J., Rosenbloom, and Jimenez, S~. (1987) Biochem. J. 247, 597-604. Roberts, C.J., Birkenmeier, T.M., McQuillan, J.J., Akiyama, S.K., Yamada, S.S., Chen, W.-T., Yamada, K.M., and McDonald, J.A. (1988) J. Biol. Chem. 263,4586-4592. K~hflri, V.-M., Peltonen, J., Chen, Y.-Q., and Uitto, J. (1991) Lab. Invest. 64,807-818. Rossi, P., Karsenty, G., Roberts, A., Roche, N., Sporn, M., and de Crombrugghe, B. (1988) Cell 52:405-414. I~hflri, V.-M., Chen, Y.-Q., Su, M.W., Ramirez, F., and Uitto, J. (1990) J. Clin. Invest. 86,1489-1495. Burgeson, R.E., Lunstrum, G.P., Rokosova, B., Rimberg, L.S., Rosenbaum, L.M., and Keene, D.R. (1990) Ann. N.Y. Acad. Sci. 580,32-43. Keene, D.R., Sakai, L.Y., Lunstrum, G.P., Morris, N.P., and Burgeson, R.E. (1987) J. CeU Biol. 104, 611-621. 679

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Transforming growth factor-beta up-regulates type VII collagen gene expression in normal and transformed epidermal keratinocytes in culture.

Transforming growth factor-betas (TGF-betas) have been shown to enhance the expression of extracellular matrix genes, including several collagens. In ...
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