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Regulation of Extracellular Matrix Remodeling Associated With Pelvic Organ Prolapse

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©2010 Taipei Medical University

R E V I E W A R T I C L E

Pelvic organ prolapse (POP), like stress urinary incontinence, has a significant impact on women’s quality of life. POP results from a defect of the uterosacral/cardinal ligament com-plex, anterior vaginal wall, and other supportive tissues. However, there is a paucity of information about the etiology and pathophysiology of POP because of its multifactorial and heterogeneous risk factors. Recent reports of women with POP identified changes in the status of the connective tissue, of which the extracellular matrix (ECM) comprises the major component. Accelerated remodeling in patients with POP is caused by biochemical changes of the ECM, e.g., collagen, elastin, and stromal cells. Myofibroblasts play a role in ECM remodeling and can be modulated by matricellular regulators, e.g., transformation growth factor (TGF)-β, thrombospondin (TSP)-1, and matrix metalloproteases (MMPs). The homeostasis of MMPs with the lysyl oxidase family and fibulin ensure ECM integrity. Disturbances in the balance between synthesis/assembly and degradation of ECM pro-teins in the pelvic floor may result in POP. The high recurrence rate after pelvic reconstruc-tive surgery necessitates the use of an adjuvant synthetic mesh. With the establishment of an in vitro model, our study showed that the interplay among the ECM, myofibroblasts, and a synthetic mesh can determine the usefulness of the synthetic mesh in pelvic recon-structive surgery. It was hypothesized that accelerated remodeling in patients with POP is caused by biochemical changes in ECM proteins, myofibroblasts, and their regulators. Further studies are needed to elucidate the following issues: first, whether women with POP have abnormal synthesis and/or degradation of the ECM, and different amounts of stromal cells (myofibroblasts); second, whether myofibroblasts exhibit different ECM pro-tein productions under the regulation of MMP, TSP-1, and TGF-β; and third, whether ECM matricellular proteins, e.g., TSP-1 and TGF-β, can modulate the biologic responses of host stromal cells to a synthetic mesh used in pelvic reconstructive surgery. This will be very informative for the further advancement of our understanding and treatment of pelvic floor reconstruction.

Received: Sep 14, 2009 Revised: Dec 9, 2009 Accepted: Dec 15, 2009

KEY WORDS:

extracellular matrix (ECM); matrix metalloprotease (MMP);

myofibroblasts;

pelvic organ prolapse (POP); thrombospondin (TSP)-1; transformation growth factor (TGF)-β

Regulation of Extracellular Matrix Remodeling

Associated With Pelvic Organ Prolapse

Ming-Ping Wu

1,2

*

1Division of Urogynecology and Pelvic Floor Reconstruction, Department of Obstetrics and Gynecology, Chi Mei Foundation Hospital, Tainan, Taiwan

2Department of Obstetrics and Gynecology, College of Medicine, Taipei Medical University, Taipei, Taiwan

*Corresponding author. Director, Division of Urogynecology and Pelvic Floor Reconstruction, Department of Obstetrics and Gynecology, Chi Mei Foundation Hospital, 901 Chung Hwa Road, Yung Kang City, Tainan 710, Taiwan.

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1. Pelvic Organ Prolapse is Associated With

Abnormal Extracellular Matrix

Homeostasis

Pelvic organ prolapse (POP), like stress urinary in-continence (SUI), is prevalent in women, adversely af-fects their quality of life, and worsens with age. In the Women’s Health Initiative study, 41% of women aged 50–79 years showed some degree of POP, including cystoceles (34%), rectoceles (19%), and uterine prolapse (14%).1 The anterior vaginal wall and the uterosacral ligament/cardinal complex are the main support tis-sues for the bladder base and uterus (or vaginal stump), respectively. POP and/or SUI can have a significant im-pact on women’s quality of life. Pelvic connective tissue resilience decreases with vaginal delivery, menopause, physical labor, chronic lung diseases, and so on.2 The prevalence of POP increases as women age. The life-time risk of undergoing prolapse or continence surgery is 11.1%, with a high recurrence and a necessity for re-operation of up to 29.2%.3 There are some risk factors for POP recurrence, e.g., poor tissue quality, impaired healing, chronic diseases with persistent high intra-abdominal pressure (due to obstructive pulmonary disease, asthma, or constipation), and age 60 years or above.4 POP is caused by mechanical, myogenic, neu-rological, and connective tissue factors. Although some reports identified changes in the connective tissue sta-tus in women with POP and/or SUI, there is a paucity of information about the etiology and pathophysiology.

A possible relationship between POP and connec-tive tissue was indirectly implied by the repeated as-sociation of clinically significant POP and connective tissue diseases, e.g., Marfan or Ehlers-Danlos syndrome with joint hypermobility.5,6 Normal connective tissue contains relatively few cells with abundant extracel-lular matrix (ECM). The ECM is made up of water, col-lagen, elastin, and a ground substance, which are produced by fibroblasts. POP results from ECM altera-tions, e.g., collagen (types I, III, IV, V, and VI), elastin, and glycoproteins (fibronectin, vitronectin, and laminin), as well as the recruitment of stromal cells, e.g., fibroblasts, endothelial cells, and inflammatory cells.7 Collagen fibers form the structural framework and the resisting tensile force of tendons.8 Connective tissue alterations might eventually lead to failure of even the most technically sound POP repair.

Collagen types I and III are the two main constituents of interstitial connective tissue. Type I collagen is ubiq-uitous, with large amounts present in the skin, ligaments, fascia, organ capsules, cartilage, and tendons. Type III collagen is abundant in loose connective tissue, e.g., the skin, uterus, aorta, lungs, and ligaments. Type III col-lagen is the initial colcol-lagen laid down in wound healing and is usually replaced by type I collagen over several months.8 Types I and III have distinct physical properties and their relative proportions influence tissue functions.

Type I is responsible for the mechanical strength in con-nective tissues, whereas type III appears to play a role in tissue elasticity and extensibility.9 However, changes in collagen subtypes remain controversial according to different literature. Moalli et al reported increased type III collagen in the full-thickness vaginal apex in women with POP relative to those without POP.10 They suggested that this tissue is actively remodeled under biomechan-ical stresses associated with POP. Gabriel et al also re-ported that type III collagen expression in the uterosacral ligament was significantly increased related to the pres-ence of POP (p < 0.001) rather than age or parity.9 The higher type III expression or the decrease in the type I/III ratio might adversely weaken the tensile strength and elasticity of pelvic tissues, with no difference in colla-gen I expression.9 On the contrary, Lin et al reported that there was significantly less type III collagen in the anterior vaginal wall of women with POP. The quantita-tive immunoreactivities of collagen types I and III had significant positive correlations with aging, but not with POP itself.7 Liapis et al also reported a similar find-ing after assessfind-ing the uterosacral ligament in women with POP.11 Compared to elastin, which allows the tis-sue to stretch and elongate up to 70% of its length and return to its original contour, unruptured collagen can elongate only 4% prior to failure.8 Klutke et al reported altered metabolism and a significant decrease in elas-tin in the uterosacral ligament of women with POP.12

2. ECM Remodeling is Regulated by

Matricellular Regulators

Matrix metalloproteases (MMPs) are key regulators of connective tissue degradation, which are involved in physiologic and pathologic processes, including wound healing, tissue remodeling,13 tumor invasion, and tumor metastasis.14 MMPs are a family of highly conserved, zinc-dependent endopeptidases that maintain the turn-over of connective tissues throughout the body.15 They regulate many biologic processes through the release, activation, or sequestration of growth factors, growth factor-binding proteins, cell surface receptors, and cell-cell adhesion molecules.14 These enzymes are critically involved in the devastating effect of ECM remodeling and in the healing process of injured ligaments.16 Mod-ulation of the ECM microenvironment can potentially change cell-matrix interactions associated with cell movement. This highlights the importance of ECM re-modeling in physiologic and pathologic conditions. Among MMP family members, MMP-2 is a ubiquitous, largely constitutively expressed enzyme, while the expression of MMP-9 tends to be more localized and regulated. Moalli et al found increased activation of MMP-9 expression, but no change in the expressions of proMMP-9, proMMP-2, or active MMP-2, using quantita-tive zymography in histologically confirmed full-thickness

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vaginal specimens in patients with POP.10 Phillips et al found an increase in proMMP-2 expression but no dif-ference in active MMP-2 or proMMP-9 expressions using zymography in full-thickness vagina in patients with POP.17 Gabriel et al found increased active MMP-2, but not MMP-1, expression in the uterosacral ligament by immunohistochemistry in patients with POP.18 The dif-ference in these results most likely reflects the dispa-rate tissues targeted for analysis and different methods of protein quantification. In summary, epithelial speci-mens showed high MMP-2 levels,17 while subepithelial, muscularis, and adventitia specimens showed high MMP-9 levels.10 All of the data point to a condition in which the remodeling of connective tissue is acceler-ated in the vagina and supportive tissues in women with POP relative to control subjects.15 The activities of MMPs are regulated by endogenous inhibitors referred to as tissue-derived inhibitors of metalloproteases (TIMPs), transformation growth factor (TGF)-β, and thrombo-spondin (TSP)-1.13 Increased MMP expressions, which parallel significant reductions of TIMPs affect collagen turnover in women with POP.19,20 TGF-β transforms epi-thelial cells and activates MMP production during path-ologic conditions.21,22 TSP-1 inhibits the activities of MMP-2 and MMP-9 via direct interactions with these proteases in specific regions.23,24 Modulation of the ECM microenvironment can potentially change cell-matrix interactions associated with cell movement, which highlights the importance of ECM remodeling in physi-ologic and pathphysi-ologic conditions.

Another research field is the homeostasis between the lysyl oxidase (LOX) family and fibulin.25 LOXs are ex-tracellular copper-dependent monoamine oxidases, se-creted by fibroblasts and smooth muscles. LOXs catalyze a key step in the posttranslational cross-linking of elastin and an element of the scaffold to ensure spatially defined deposition of elastin. Fibulin is a calcium-dependent elastin-binding protein, and it determines the elastic fiber organization. LOX-like 1 (LOXL1) protein specifically localizes to sites of elastogenesis and interacts with fibulin-5.25 The failure of elastic fiber homeostasis leads to POP.26 Reductions in the mRNA and protein expres-sion levels of LOX family enzymes were noted in women with POP.25 Collectively, these alterations in ECM proteins may play specific biochemical roles in the etiology of POP.26 MMPs, as well as TIMPs, are in homeostasis with the LOX family and fibulin to ensure the ECM’s integrity. Disturbances in the balance between the synthesis/ assembly and degradation of ECM proteins in the pelvic floor during aging and parturition may result in POP.

3. Myofibroblasts Play Important Roles in

ECM Remodeling During POP Processes

Fibroblasts are the major cellular component of the ECM. Their biologic behaviors significantly affect

ECM remodeling. Alpha-smooth muscle actin ( α-SMA)-containing contractile fibroblastic cells, i.e., myofibro-blasts and activated fibromyofibro-blasts, were identified as playing possible roles during healing processes by re-storing tissues in situ via ECM contraction.27 The ap-pearance of differentiated myofibroblasts may have multiple origins in different pathological situations.28 Myofibroblasts are involved in maintaining tissue ho-meostasis in both the intact and remodeled anterior cruciate ligament.29 It is generally accepted that modu-lation of fibroblastic cells towards the myofibroblastic phenotype, with acquisition of specialized contractile features, is essential for connective tissue remodeling during normal and pathological wound healing.30 Yet myofibroblasts still remain one of the most enigmatic of cells, because of their transient appearance in as-sociation with connective-tissue injury and difficulties in establishing their role in the production of tissue contracture.30

Myofibroblasts can be regulated by ECM matricel-lular regulators, e.g., TGF-β and TSP-1. TGF-β is a potent fibroblast activation and transdifferentiation factor.31 Myofibroblast contraction can activate latent TGF-β from the ECM.32 In our previous study, TGF-β activated fibroblasts with migratory ability, as well as the α-SMA expression level, a typical marker of myofibroblasts.33 TSP-1 potently exerts an inhibitory effect on the migra-tion and invasion of myofibroblasts, but has little effect on the α-SMA expression level.33 In addition to the in-hibitory effects on myofibroblasts, TSP-1 inhibits the activities of MMP-2 and MMP-9 via direct interactions with these proteases in specific regions.23,24 Therefore, TSP-1 can potentially affect ECM remodeling via two aspects, by inhibiting fibroblast migration34 and mod-ulating MMPs.33

4. The Biological Response of Host Stromal

Cells to a Synthetic Mesh is Unclear

The high recurrence rate after pelvic reconstructive surgery necessitates the development of more-refined reconstructive surgical methods.3 Although the use of synthetic prostheses for sacrocolpopexy is well es-tablished, the use of prostheses for repair of isolated anterior and posterior compartment defects remains controversial. Several lines of research have suggested that autologous tissues used in pelvic reconstructive surgery are themselves altered and weakened in women with POP.35,36 Whether those tissue alterations are pri-mary or secondary to the pelvic floor disorder remains unknown. There are no long-term studies with suffi-cient patient numbers to draw conclusions as to which current prosthesis, either synthetic or biological, is su-perior for vaginal surgery. Tension-free vaginal meshes (TVMs) with procedural kits which include disposable insertion needles, retrieval devices, and large pieces of

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polypropylene mesh are increasingly being adopted. The available products at present include intravaginal slingplasty (IVS) (Tyco Healthcare, Norwalk, CT, USA), Prolift (Ethicon, Somerville, NJ, USA), Perigee, Apogee, Elevate (American Medical Systems, Minnetonka, MN, USA), and Avaulta (Bard, Gainesville, VA, USA). Some authors have already described their success perform-ing this type of repair;37 nevertheless, great care and consideration should be devoted to actual and theo-retical short- and long-term risks, many of which have not been fully elucidated.

Our recent review showed that patients with primary and those with recurrent POP may benefit from the use of adjuvant materials in pelvic reconstructive surgery.38 Different prostheses, either synthetic (absorbable, non-absorbable, or mixed) or biologic (autologous, allograft, or xenograft donor tissue), have emerged as adjuvant materials for the purpose of integrating with host tis-sues and supporting attenuated areas.39 However, ideal materials to achieve the goals of being sterile, durable, non-carcinogenic, inexpensive, easily applied, and caus-ing no antigenic response but able to withstand re-modeling by body tissue are not yet available.38,40 A successful material can decrease the operating time and morbidity in vaginal surgeries and decrease the higher hospital costs and higher risks of abdominal procedures. Some issues in the use of prostheses in pelvic floor reconstructive surgery are still being de-bated. Knowledge of the mechanism between the host response and a prosthesis is still limited at present. A recent study revealed that fibroblasts surrounding mesh material displayed strong MMP-2 gene transcrip-tion, whereas fibroblasts without close contact to the mesh material had low MMP-2 synthesis rates. In vitro studies support a cellular crosstalk concept between fibroblasts and the ECM. The zonal and cell-specific regulation of MMP-2 gene transcription illuminates an intimate cellular crosstalk in a foreign-body reaction that may provide a new approach for mesh modifica-tion.41 Fibroblast proliferation, neovascularization, and remodeling occur with a graft. No evidence of an inflam-matory reaction or graft degeneration was detected.42 Therefore, the usefulness of a mesh is dependent on the ingrowth of fibroblasts and other stromal cells. The establishment of in vivo and in vitro study models is im-portant to understand the pathophysiology of POP and synthetic meshes and biologic grafts used in pelvic floor reconstruction.

5.

Different In Vitro or In Vivo Models Have

Been Developed to Elucidate the ECM

Microenvironment

Different animal models are being used to characterize the biomechanical properties of the pelvic support, including non-human primates, rodents, rabbits, and

sheep.43 The organization of the extracellular com-ponents, i.e., ECM, myofibroblast, and endothelial cell co-culture system can distinguish characteristics of dif-ferent synthetic materials that are associated with con-structive tissue remodeling.44 Common features of this ECM-assisted tissue remodeling include angiogenesis, recruitment of circulating progenitor cells, and con-structive remodeling of damaged tissue structures.45 To elucidate the biological behaviors of host stromal cell responses to different synthetic meshes, we estab-lished an in vitro Matrigel multicellular co-culture sys-tem with an embedded synthetic mesh,46 which was modified from a report by Walter-Yohrling et al47 and our previous work.33 We used NIH3T3 to represent myo-fibroblasts because of its characters of high α-SMA ex-pression and MMP-2 activity compared to normal primary fibroblasts. NIH3T3 cells, endothelial cells, or both cells were dispersed in the Matrigel multicellular co-culture system with or without different meshes being embedded. NIH3T3 cells and endothelial cells grew into the interstitials of the mesh and formed a tube-like structure. Many more NIH3T3 cells and/or en-dothelial cells were recruited into the pores of the type I Prolift (J&J) mesh than in the type III IVS (Tyco) mesh embedding system (Figure 1).46 The presence of a syn-thetic mesh may also hinder stromal cell recruitment. The impaired recruitment and tube-formation ability of myofibroblasts and endothelial cells into the type III mesh, compared to the type I mesh, may account, at least in part, for the limitations of these meshes. Es-tablishment of this in vitro Matrigel co-culture system is therefore important for understanding the patho-physiology of POP and synthetic meshes and biologic grafts used in pelvic reconstructive surgery. Gaining a better understanding of the complexities of ECM-myofibroblast interactions will improve our prospects for developing more effective pelvic reconstructive surgical techniques.

6.

Future Directions

It was hypothesized that accelerated remodeling in patients with POP is caused by biochemical changes in ECM proteins, myofibroblasts, and their regulators. Further studies are indicated to elucidate the following issues: first, whether women with POP have abnormal synthesis and/or degradation of the ECM, and different amounts of stroma cells (myofibroblasts); second, whether myofibroblasts from women with POP have different ECM protein productions under regulation

of MMP, TSP-1, and TGF-β; and third, whether ECM

matricellular proteins, e.g., TSP-1 and TGF-β, can mod-ulate the biologic responses of host stromal cells to synthetic meshes in pelvic reconstructive surgery. The interplay of the ECM, myofibroblasts, and synthetic meshes can determine the usefulness and development

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of synthetic prostheses in pelvic reconstructive surgery. This will be very informative for the further advance-ment of our understanding and treatadvance-ment using pelvic floor reconstruction.

References

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Figure 1 Myofibroblasts (NIH3T3), endothelial cells (human umbilical vein endothelial cells; HUVECs), or both cells of same

number were dispersed in a Matrigel co-culture system with or without different embedded meshes for 1 and 24 hours. Many more NIH3T3s were recruited into the pores of the type I mesh, e.g., Prolift (J&J), than into the type III mesh, IVS, (Tyco) embed-ding system at 24 hours. Similar phenomena were also found in both HUVECs and stromal cells (merged image shown in the right lower panel). Matrigel without a mesh was used as a positive control. The presence of the synthetic mesh may also hinder the recruitment of stromal cells (unpublished data, presented at The 34th Annual Meeting of the International Urogynecology

Association, Como, Italy).46

3T3 HUVEC

IVS

Blight field 3T3 HUVEC

1 hr

24 hr

No mesh

Blight field 3T3 HUVEC

Prolift Blight field IVS Prolift No mesh 1 hr 24 hr

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34. Streit M, Velasco P, Riccardi L, Spencer L, Brown LF, Janes L, Lange-Asschenfeldt B, et al. Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice. EMBO J 2000;19:3272–82.

35. Kohli N, Miklos JR. Use of synthetic mesh and donor grafts in gynecologic surgery. Curr Womens Health Rep 2001;1:53–60. 36. Kerkhof MH, Hendriks L, Brolmann HA. Changes in connective

tissue in patients with pelvic organ prolapse—a review of the current literature. Int Urogynecol J Pelvic Floor Dysfunct 2009;20: 461–74.

37. Reisenauer C, Kirschniak A, Drews U, Wallwiener D. Anatomical conditions for pelvic floor reconstruction with polypropylene implant and its application for the treatment of vaginal pro-lapse. Eur J Obstet Gynecol Reprod Biol 2007;131:214–25. 38. Wu MP, Huang KH, Long CY, Huang KF, Yu KJ, Tang CH. The

distri-bution of different surgical types for female stress urinary incon-tinence among patients’ age, surgeons’ specialties and hospital accreditations in Taiwan: a descriptive 10-year nationwide study. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:1639–46.

39. Birch C, Fynes MM. The role of synthetic and biological pros-theses in reconstructive pelvic floor surgery. Curr Opin Obstet Gynecol 2002;14:527–35.

40. Karlovsky ME, Kushner L, Badlani GH. Synthetic biomaterials for pelvic floor reconstruction. Curr Urol Rep 2005;6:376–84. 41. Jansen PL, Kever M, Rosch R, Krott E, Jansen M, Alfonso-Jaume A,

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數據

Figure 1  Myofibroblasts (NIH3T3), endothelial cells (human umbilical vein endothelial cells; HUVECs), or both cells of same

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