- Email: [email protected]
Expression of cathepsin K in neurofibromatosis 1-associated cutaneous malignant peripheral nerve sheath tumors and neurofibromas
Letters to the Editor / Journal of Dermatological Science 58 (2010) 217–231
Acknowledgements This work was financially supported by Grants from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. The authors wish to thank Ms. Akiko Nishioka for technical assistance.
227
psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 2005;174:164–73. [9] Goodman WA, Levine AD, Massari JV, Sugiyama H, McCormick TS, Cooper KD. IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells. J Immunol 2009;183:3170–6. [10] Hedrick MN, Lonsdorf AS, Shirakawa AK, Richard Lee CC, Liao F, Singh SP, et al. CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. J Clin Invest 2009;119:2317–29.
References [1] Blauvelt A. T-helper 17 cells in psoriatic plaques and additional genetic links between IL-23 and psoriasis. J Invest Dermatol 2008;128:1064–7. [2] Zaba LC, Fuentes-Duculan J, Eungdamrong NJ, Abello MV, Novitskaya I, Pierson KC, et al. Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells. J Invest Dermatol 2009;129:79–88. [3] Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 2007;445:866–73. [4] Wolk K, Haugen HS, Xu W, Witte E, Waggie K, Anderson M, et al. IL-22 and IL20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-g are not. J Mol Med 2009;87:523–36. [5] Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007;449:564–9. [6] Torii K, Maeda A, Saito C, Furuhashi T, Shintani Y, Shirakata Y, et al. UVB wavelength dependency of antimicrobial peptide induction for innate immunity in normal human keratinocytes. J Dermatol Sci )2009;(August) [Epub ahead of print]. [7] Saito C, Maeda A, Morita A. Bath-PUVA therapy induces circulating regulatory T cells in patients with psoriasis. J Dermatol Sci 2009;53:231–3. [8] Sugiyama H, Gyulai R, Toichi E, Garaczi E, Shimada S, Stevens SR, et al. Dysfunctional blood and target tissue CD4+CD25 high regulatory T cells in
Yuan-Hsin Lo Kan Torii Chiyo Saito Takuya Furuhashi Akira Maeda* Akimichi Morita Department of Geriatric and Environmental Dermatology, Nagoya City University, Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan *Corresponding
author. Tel.: +81 52 853 8261; fax: +81 52 852 5449 E-mail addresses: [email protected], [email protected] (A. Maeda) 10 November 2009 doi:10.1016/j.jdermsci.2010.03.018
Letter to the Editor Expression of cathepsin K in neurofibromatosis 1-associated cutaneous malignant peripheral nerve sheath tumors and neurofibromas Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that affects about 1 in 3500 individuals worldwide. About 8–13% of patients with NF1 develop malignant peripheral nerve sheath tumors (MPNST) which generally arise from plexiform neurofibromas (pNF) and often have a poor prognosis [1]. Cutaneous MPNSTs are rare entities compared with their deep soft tissue counterparts [2]. Because of their superficial location within the dermis and subcutis, they are easily overlooked, leading to a delay in the diagnosis of malignant transformation which adversely affects the patient’s prognosis. Therefore, it is of critical importance to distinguish MPNST from NF. Cathepsin K, a cysteine protease with strong collagenolytic and elastolytic properties involved in extracellular matrix turnover, was first demonstrated to play an essential role in osteoclast-mediated bone resorption [3]. Cathepsin K has been shown to be highly active and potent in degrading extracellular matrix proteins and was found to be overexpressed in several malignant tumors, such as breast cancer cells [4] and malignant melanoma [5]. Inhibition of cathepsin K resulting in decreased invasion of melanoma cell lines further suggests a crucial role of cathepsin K in tumor invasion and metastasis [5]. The present study investigated the expression of cathepsin K in cutaneous MPNST and NF. Formalin-fixed, paraffin-embedded tissues were available for 40 cases of NF and 6 cases of cutaneous MPNST that were clinically and histologically typical and all obtained from NF1 patients. The 40 cases of NF included 11 localized neurofibromas, 11 diffuse neurofibromas (dNF) and 18 pNF (18 female and 22 male) patients with an average age of 31.2 (range: 7–88). The 6 cases of cutaneous
MPNST included 2 female and 4 male patients with an average age of 61.0 (range: 30–88). All six cutaneous MPNST cases had a history of NF1 and developed in pre-existing neurofibromas. All the cases were analyzed for immunohistochemical expression of cathepsin K (mouse mAb, clone 3F9; 1:500 dilution; Biovendor, USA) and Ki-67 nuclear proliferation-related antigen (mouse mAb, clone 7B11; pre-diluted; Invitrogen, USA). Immunostaining was scored semiquantitatively based on the percentage of spindle tumor cells stained: 0 (<5%), 1 (5–25%), 2 (26–50%), 3 (51–75%) or 4 (>76%). The results of immunohistochemical studies with antibodies for cathepsin K and Ki-67 are shown in Fig. 1 and detailed in Table 1. In six cutaneous MPNST cases, cases 1 and 4 showed scattered sarcomatous areas that were surrounded by neurofibromatous areas. In cases 2, 5 and 6, the sarcomatous components were located within the central region of the entire tumor. Microscopically, in case 3, the sarcomatous area was composed of spindle cells arranged in fascicles adjacent to the neurofibromatous area (Fig. 1). We detected the expression of cathepsin K in all six MPNSTs but not in NFs. Positive reactions to cathepsin K were observed only in the MPNST areas, but not in the surrounding NF areas (Fig. 1, cases 2 and 3), while Ki-67-positive signals somewhat distinguished the NF areas from the MPNST areas since the former lesions are always Ki-67 negative [6]. All MPNSTs demonstrated strong cathepsin K positivity (4+) compared to weak or moderate Ki-67 nuclear positivity (1+ or 2+) (Table 1). Stratum corneum, hair follicles and sebaceous glands were immunopositive for cathepsin K, which served as positive control. In addition, the tumor cells of three out of six cases of MPNSTs were positive for S-100 protein stain, while the other three cases were negative. It is well known that degradation of the extracellular matrix is a pivotal step for tumor cell invasion and development of metastasis. Matrix metalloproteinases (MMPs), which can be
Letters to the Editor / Journal of Dermatological Science 58 (2010) 217–231
228
Table 1 Semiquantitative results for cathepsin K and Ki-67 immunohistochemical staining in 40 cases of NF and 6 cases of MPNST.
Localized NF dNF pNF MPNSTs
n
Cathepsin K
Ki-67
0
1
2
3
4
0
1
2
3
4
11 11 18 6
11 11 18 0
0 0 0 0
0 0 0 0
0 0 0 0
0 0 0 6
11 11 18 0
0 0 0 3
0 0 0 3
0 0 0 0
0 0 0 0
Reactivity score: % of positive tumor cells scored as 0 (<5%), 1 (5–25%), 2 (26–50%), 3 (51–75%) and 4 (>76%).
expressed either by tumor cells or by surrounding stromal cells, have been shown to be strongly associated with cancers as they contribute to degradation of the extracellular matrix and, therefore, play important roles in tumor invasion and metastasis [7,8]. MMP-13 was found to be expressed in more than half of
the MPNSTs and were associated with tumor progression [1]. However, the most potent matrix-degrading protease, cathepsin K, has not been studied in MPNST. Cathepsin K can degrade a wide range of collagens, cleaving at multiple sites with the triple helix of collagens type I and III as well
Fig. 1. Representative images of immunohistochemical examination with cathepsin K and Ki-67. Expression patterns of NF and MPNST of three different NF1 patients are shown (cases 1, 2 and 3). Cathepsin K is negative in all NFs (left column), but strongly expressed in tumor cells of MPNST (center column). Cathepsin K positive cells were present in the MPNST areas (top right area in cases 2 and 3), but not in the NF areas (bottom left area of cases 2 and 3). Ki-67 (1+ or 2+) nuclear positivity was shown in MPNST (right column). Original magnification, 200.
Letters to the Editor / Journal of Dermatological Science 58 (2010) 217–231
as at extra-helical regions, and thus has a much higher potency than MMPs [9]. Here, we describe, to our knowledge for the first time, expression of cathepsin K in cutaneous MPNST, but not in NF. Cathepsin K expression in MPNST cells might mediate extracellular matrix degradation, thereby promoting tumor cell invasion. Although the pathogenetic role of cathepsin K in MPNST remains unclear, the marked expression of cathepsin K suggests its biologic importance in the transformation and progression of MPNST, as well as its usefulness as a reliable marker. Considering the absence of cathepsin K in NF, cathepsin K may be an attractive therapeutic target for treating MPNST.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jdermsci.2010.04.005. References [1] Holtkamp N, Atallah I, Okuducu AF, Mucha J, Hartmann C, Mautner VF, et al. MMP-13 and p53 in the progression of malignant peripheral nerve sheath tumors. Neoplasia 2007;9:671–7. [2] Coady MS, Polacarz S, Page RE. Cutaneous malignant peripheral nerve sheath tumour (MPNST) of the hand: a review of current literature. J Hand Surg Br 1993;18:478–81. [3] Drake FH, Dodds RA, James IE, Connor JR, Debouck C, Richardson S, et al. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J Biol Chem 1996;271:12511–6. [4] Littlewood-Evans AJ, Bilbe G, Bowler WB, Farley D, Wlodarski B, Kokubo T, et al. The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res 1997;57:5386–90. [5] Quintanilla-Dieck MJ, Codriansky K, Keady M, Bhawan J, Runger TM. Cathepsin K in melanoma invasion. J Invest Dermatol 2008;128:2281–8. [6] Liapis H, Marley EF, Lin Y, Dehner LP. p53 and Ki-67 proliferating cell nuclear antigen in benign and malignant peripheral nerve sheath tumors in children. Pediatr Dev Pathol 1999;2:377–84. [7] Stetler-Stevenson WG. The role of matrix metalloproteinases in tumor invasion, metastasis, and angiogenesis. Surg Oncol Clin N Am 2001;10:383–92. [8] Curran S, Murray GI. Matrix metalloproteinases in tumour invasion and metastasis. J Pathol 1999;189:300–8. [9] Garnero P, Borel O, Byrjalsen I, Ferreras M, Drake FH, McQueney MS, et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J Biol Chem 1998;273:32347–52.
Xiaofeng Yana,b a Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan b Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
229
Masakazu Takahara* Long Dugu Lining Xie Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan Chisato Gondoa,b Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan b Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan
a
Makoto Endo Yoshinao Oda Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan Takeshi Nakahara Hiroshi Uchi Satoshi Takeuchi Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan Yating Tu Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Yoichi Moroi Masutaka Furue Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan *Corresponding
author. Tel.: +81 92 642 5585; fax: +81 92 642 5600 E-mail address: [email protected] (M. Takahara) 5 February 2010 doi:10.1016/j.jdermsci.2010.04.005
Letter to the Editor Elevated serum placenta growth factor (PlGF) levels in patients with systemic sclerosis: A possible role in the development of skin but not lung fibrosis Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular damage and excessive fibrosis of the skin and various internal organs with an autoimmune background, although disease pathogenesis remains unclear. Placenta growth factor (PlGF), originally discovered in human placenta, is a secreted dimeric glycoprotein of 46–50 kDa, highly similar to vascular endothelial growth factor (VEGF), and has been shown to be chemotactic and mitogenic for endothelial cells in
vitro [1] and angiogenic in vivo [2]. In SSc, significant elevation of PlGF and positive correlation of PlGF levels with estimated right ventricular systolic pressure were reported [3]. However, contribution of PlGF to fibrosis in SSc remains unclear. Serum samples from 53 Japanese patients with SSc (42 females and 11 males) were examined for PlGF levels in sera. All patients fulfilled the criteria for SSc proposed by the American College of Rheumatology (ACR). These patients were grouped into 28 patients with diffuse cutaneous SSc (dcSSc) and 25 patients with limited cutaneous SSc (lcSSc). As a disease control, we also examined serum samples from 10 patients with systemic lupus erythematosus (SLE) who fulfilled the ACR criteria. Fifteen age- and sex-
Acknowledgements This work was financially supported by Grants from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. The authors wish to thank Ms. Akiko Nishioka for technical assistance.
227
psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 2005;174:164–73. [9] Goodman WA, Levine AD, Massari JV, Sugiyama H, McCormick TS, Cooper KD. IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells. J Immunol 2009;183:3170–6. [10] Hedrick MN, Lonsdorf AS, Shirakawa AK, Richard Lee CC, Liao F, Singh SP, et al. CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. J Clin Invest 2009;119:2317–29.
References [1] Blauvelt A. T-helper 17 cells in psoriatic plaques and additional genetic links between IL-23 and psoriasis. J Invest Dermatol 2008;128:1064–7. [2] Zaba LC, Fuentes-Duculan J, Eungdamrong NJ, Abello MV, Novitskaya I, Pierson KC, et al. Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells. J Invest Dermatol 2009;129:79–88. [3] Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 2007;445:866–73. [4] Wolk K, Haugen HS, Xu W, Witte E, Waggie K, Anderson M, et al. IL-22 and IL20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-g are not. J Mol Med 2009;87:523–36. [5] Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007;449:564–9. [6] Torii K, Maeda A, Saito C, Furuhashi T, Shintani Y, Shirakata Y, et al. UVB wavelength dependency of antimicrobial peptide induction for innate immunity in normal human keratinocytes. J Dermatol Sci )2009;(August) [Epub ahead of print]. [7] Saito C, Maeda A, Morita A. Bath-PUVA therapy induces circulating regulatory T cells in patients with psoriasis. J Dermatol Sci 2009;53:231–3. [8] Sugiyama H, Gyulai R, Toichi E, Garaczi E, Shimada S, Stevens SR, et al. Dysfunctional blood and target tissue CD4+CD25 high regulatory T cells in
Yuan-Hsin Lo Kan Torii Chiyo Saito Takuya Furuhashi Akira Maeda* Akimichi Morita Department of Geriatric and Environmental Dermatology, Nagoya City University, Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan *Corresponding
author. Tel.: +81 52 853 8261; fax: +81 52 852 5449 E-mail addresses: [email protected], [email protected] (A. Maeda) 10 November 2009 doi:10.1016/j.jdermsci.2010.03.018
Letter to the Editor Expression of cathepsin K in neurofibromatosis 1-associated cutaneous malignant peripheral nerve sheath tumors and neurofibromas Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that affects about 1 in 3500 individuals worldwide. About 8–13% of patients with NF1 develop malignant peripheral nerve sheath tumors (MPNST) which generally arise from plexiform neurofibromas (pNF) and often have a poor prognosis [1]. Cutaneous MPNSTs are rare entities compared with their deep soft tissue counterparts [2]. Because of their superficial location within the dermis and subcutis, they are easily overlooked, leading to a delay in the diagnosis of malignant transformation which adversely affects the patient’s prognosis. Therefore, it is of critical importance to distinguish MPNST from NF. Cathepsin K, a cysteine protease with strong collagenolytic and elastolytic properties involved in extracellular matrix turnover, was first demonstrated to play an essential role in osteoclast-mediated bone resorption [3]. Cathepsin K has been shown to be highly active and potent in degrading extracellular matrix proteins and was found to be overexpressed in several malignant tumors, such as breast cancer cells [4] and malignant melanoma [5]. Inhibition of cathepsin K resulting in decreased invasion of melanoma cell lines further suggests a crucial role of cathepsin K in tumor invasion and metastasis [5]. The present study investigated the expression of cathepsin K in cutaneous MPNST and NF. Formalin-fixed, paraffin-embedded tissues were available for 40 cases of NF and 6 cases of cutaneous MPNST that were clinically and histologically typical and all obtained from NF1 patients. The 40 cases of NF included 11 localized neurofibromas, 11 diffuse neurofibromas (dNF) and 18 pNF (18 female and 22 male) patients with an average age of 31.2 (range: 7–88). The 6 cases of cutaneous
MPNST included 2 female and 4 male patients with an average age of 61.0 (range: 30–88). All six cutaneous MPNST cases had a history of NF1 and developed in pre-existing neurofibromas. All the cases were analyzed for immunohistochemical expression of cathepsin K (mouse mAb, clone 3F9; 1:500 dilution; Biovendor, USA) and Ki-67 nuclear proliferation-related antigen (mouse mAb, clone 7B11; pre-diluted; Invitrogen, USA). Immunostaining was scored semiquantitatively based on the percentage of spindle tumor cells stained: 0 (<5%), 1 (5–25%), 2 (26–50%), 3 (51–75%) or 4 (>76%). The results of immunohistochemical studies with antibodies for cathepsin K and Ki-67 are shown in Fig. 1 and detailed in Table 1. In six cutaneous MPNST cases, cases 1 and 4 showed scattered sarcomatous areas that were surrounded by neurofibromatous areas. In cases 2, 5 and 6, the sarcomatous components were located within the central region of the entire tumor. Microscopically, in case 3, the sarcomatous area was composed of spindle cells arranged in fascicles adjacent to the neurofibromatous area (Fig. 1). We detected the expression of cathepsin K in all six MPNSTs but not in NFs. Positive reactions to cathepsin K were observed only in the MPNST areas, but not in the surrounding NF areas (Fig. 1, cases 2 and 3), while Ki-67-positive signals somewhat distinguished the NF areas from the MPNST areas since the former lesions are always Ki-67 negative [6]. All MPNSTs demonstrated strong cathepsin K positivity (4+) compared to weak or moderate Ki-67 nuclear positivity (1+ or 2+) (Table 1). Stratum corneum, hair follicles and sebaceous glands were immunopositive for cathepsin K, which served as positive control. In addition, the tumor cells of three out of six cases of MPNSTs were positive for S-100 protein stain, while the other three cases were negative. It is well known that degradation of the extracellular matrix is a pivotal step for tumor cell invasion and development of metastasis. Matrix metalloproteinases (MMPs), which can be
Letters to the Editor / Journal of Dermatological Science 58 (2010) 217–231
228
Table 1 Semiquantitative results for cathepsin K and Ki-67 immunohistochemical staining in 40 cases of NF and 6 cases of MPNST.
Localized NF dNF pNF MPNSTs
n
Cathepsin K
Ki-67
0
1
2
3
4
0
1
2
3
4
11 11 18 6
11 11 18 0
0 0 0 0
0 0 0 0
0 0 0 0
0 0 0 6
11 11 18 0
0 0 0 3
0 0 0 3
0 0 0 0
0 0 0 0
Reactivity score: % of positive tumor cells scored as 0 (<5%), 1 (5–25%), 2 (26–50%), 3 (51–75%) and 4 (>76%).
expressed either by tumor cells or by surrounding stromal cells, have been shown to be strongly associated with cancers as they contribute to degradation of the extracellular matrix and, therefore, play important roles in tumor invasion and metastasis [7,8]. MMP-13 was found to be expressed in more than half of
the MPNSTs and were associated with tumor progression [1]. However, the most potent matrix-degrading protease, cathepsin K, has not been studied in MPNST. Cathepsin K can degrade a wide range of collagens, cleaving at multiple sites with the triple helix of collagens type I and III as well
Fig. 1. Representative images of immunohistochemical examination with cathepsin K and Ki-67. Expression patterns of NF and MPNST of three different NF1 patients are shown (cases 1, 2 and 3). Cathepsin K is negative in all NFs (left column), but strongly expressed in tumor cells of MPNST (center column). Cathepsin K positive cells were present in the MPNST areas (top right area in cases 2 and 3), but not in the NF areas (bottom left area of cases 2 and 3). Ki-67 (1+ or 2+) nuclear positivity was shown in MPNST (right column). Original magnification, 200.
Letters to the Editor / Journal of Dermatological Science 58 (2010) 217–231
as at extra-helical regions, and thus has a much higher potency than MMPs [9]. Here, we describe, to our knowledge for the first time, expression of cathepsin K in cutaneous MPNST, but not in NF. Cathepsin K expression in MPNST cells might mediate extracellular matrix degradation, thereby promoting tumor cell invasion. Although the pathogenetic role of cathepsin K in MPNST remains unclear, the marked expression of cathepsin K suggests its biologic importance in the transformation and progression of MPNST, as well as its usefulness as a reliable marker. Considering the absence of cathepsin K in NF, cathepsin K may be an attractive therapeutic target for treating MPNST.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jdermsci.2010.04.005. References [1] Holtkamp N, Atallah I, Okuducu AF, Mucha J, Hartmann C, Mautner VF, et al. MMP-13 and p53 in the progression of malignant peripheral nerve sheath tumors. Neoplasia 2007;9:671–7. [2] Coady MS, Polacarz S, Page RE. Cutaneous malignant peripheral nerve sheath tumour (MPNST) of the hand: a review of current literature. J Hand Surg Br 1993;18:478–81. [3] Drake FH, Dodds RA, James IE, Connor JR, Debouck C, Richardson S, et al. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J Biol Chem 1996;271:12511–6. [4] Littlewood-Evans AJ, Bilbe G, Bowler WB, Farley D, Wlodarski B, Kokubo T, et al. The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res 1997;57:5386–90. [5] Quintanilla-Dieck MJ, Codriansky K, Keady M, Bhawan J, Runger TM. Cathepsin K in melanoma invasion. J Invest Dermatol 2008;128:2281–8. [6] Liapis H, Marley EF, Lin Y, Dehner LP. p53 and Ki-67 proliferating cell nuclear antigen in benign and malignant peripheral nerve sheath tumors in children. Pediatr Dev Pathol 1999;2:377–84. [7] Stetler-Stevenson WG. The role of matrix metalloproteinases in tumor invasion, metastasis, and angiogenesis. Surg Oncol Clin N Am 2001;10:383–92. [8] Curran S, Murray GI. Matrix metalloproteinases in tumour invasion and metastasis. J Pathol 1999;189:300–8. [9] Garnero P, Borel O, Byrjalsen I, Ferreras M, Drake FH, McQueney MS, et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J Biol Chem 1998;273:32347–52.
Xiaofeng Yana,b a Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan b Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
229
Masakazu Takahara* Long Dugu Lining Xie Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan Chisato Gondoa,b Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan b Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan
a
Makoto Endo Yoshinao Oda Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan Takeshi Nakahara Hiroshi Uchi Satoshi Takeuchi Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan Yating Tu Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Yoichi Moroi Masutaka Furue Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan *Corresponding
author. Tel.: +81 92 642 5585; fax: +81 92 642 5600 E-mail address: [email protected] (M. Takahara) 5 February 2010 doi:10.1016/j.jdermsci.2010.04.005
Letter to the Editor Elevated serum placenta growth factor (PlGF) levels in patients with systemic sclerosis: A possible role in the development of skin but not lung fibrosis Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular damage and excessive fibrosis of the skin and various internal organs with an autoimmune background, although disease pathogenesis remains unclear. Placenta growth factor (PlGF), originally discovered in human placenta, is a secreted dimeric glycoprotein of 46–50 kDa, highly similar to vascular endothelial growth factor (VEGF), and has been shown to be chemotactic and mitogenic for endothelial cells in
vitro [1] and angiogenic in vivo [2]. In SSc, significant elevation of PlGF and positive correlation of PlGF levels with estimated right ventricular systolic pressure were reported [3]. However, contribution of PlGF to fibrosis in SSc remains unclear. Serum samples from 53 Japanese patients with SSc (42 females and 11 males) were examined for PlGF levels in sera. All patients fulfilled the criteria for SSc proposed by the American College of Rheumatology (ACR). These patients were grouped into 28 patients with diffuse cutaneous SSc (dcSSc) and 25 patients with limited cutaneous SSc (lcSSc). As a disease control, we also examined serum samples from 10 patients with systemic lupus erythematosus (SLE) who fulfilled the ACR criteria. Fifteen age- and sex-