Failure of Pelvic Organ Support in Mice Deficient In Fibulin-3

Rahn, David D.; Acevedo, Jesús F.; Roshanravan, Shayzreen M.; Keller, Patrick W.; Davis, Elaine C.; Marmorstein, Lihua Y.; Word, R. Ann

doi:10.2353/ajpath.2009.080212

Cited by 75 publications

(71 citation statements)

References 36 publications

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“…However, these animals experience normal tissue recovery following parturition. This latter finding could be related to the observed compensatory increase in mRNA transcripts for protease inhibitors (TIMP1, TIMP3), fibulin-5, and tropoelastin (9).…”

Section: Murine Models Of Popmentioning

confidence: 92%

“…Fibulin-3-knockout mice (Fbln3 -/-) have abdominal wall fascial defects and variably develop POP that increases with age. Moreover, the Fbln3 -/-animals that exhibit POP also have increased levels of active MMP-2 and MMP-9 compared with Fbln3 -/-animals without prolapse or WT animals (9). However, these animals experience normal tissue recovery following parturition.…”

Section: Murine Models Of Popmentioning

confidence: 99%

“…The seven known members of the fibulin family (fibulins 1-7) have a series of EGF-like domains followed by a C-terminal "fibulin-type" domain (22). Both fibulin-3 and fibulin-5 have been implicated as having a role in maintaining pelvic support (8,9). Fibulin-3-knockout mice (Fbln3 -/-) have abdominal wall fascial defects and variably develop POP that increases with age.…”

Section: Murine Models Of Popmentioning

confidence: 99%

“…It is estimated that 11%-19% of women will require surgical repair in their lifetime to treat prolapse, and approximately one-third of these will require additional surgery for recurrent disease (5); thus it is important to define the molecular and cellular mecha-nisms of POP. Because of the difficulty of procuring human tissue and the expense associated with studying POP in primates (6), rodent models of elastinopathies have been used to study this disease (7)(8)(9). While rodents are quadrupeds and, by definition, have different forces operating on the pelvic floor, the connective tissue anatomy is grossly similar to that seen in humans (10).…”

mentioning

confidence: 99%

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Fibulin-5: two for the price of one maintaining pelvic support

Northington

2011

J. Clin. Invest.

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Section: Murine Models Of Popmentioning

confidence: 92%

Section: Murine Models Of Popmentioning

confidence: 99%

Section: Murine Models Of Popmentioning

confidence: 99%

mentioning

confidence: 99%

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Fibulin-5: two for the price of one maintaining pelvic support

Northington

2011

J. Clin. Invest.

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“…In contrast to an observation that rectal prolapse is frequently associated with the presence of chronic inflammatory bowel disease (5), POP has been found in animals with defective ECM proteins, including fibulin-3, fibulin-5, and lysyl oxidaselike-1 (LOXL-1) (an enzyme that predominantly catalyzes crosslinking of elastin) (6)(7)(8). Interestingly, these proteins are abundantly expressed in the vaginal wall and involved in synthesis and assembly of elastic fibers.…”

Section: Introductionmentioning

confidence: 88%

Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans

Budatha¹,

Roshanravan²,

Zheng³

et al. 2011

J. Clin. Invest.

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131

132

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Pelvic organ prolapse (POP) is a common condition affecting almost half of women over the age of 50. The molecular and cellular mechanisms underlying this condition, however, remain poorly understood. Here we have reported that fibulin-5, an integrin-binding matricellular protein that is essential for elastic fiber assembly, regulated the activity of MMP-9 to maintain integrity of the vaginal wall and prevented development of POP. In murine vaginal stromal cells, fibulin-5 inhibited the β 1 integrin-dependent, fibronectin-mediated upregulation of MMP-9. Mice in which the integrin-binding motif was mutated to an integrin-disrupting motif (Fbln5 RGE/RGE ) exhibited upregulation of MMP-9 in vaginal tissues. In contrast to fibulin-5 knockouts (Fbln5 -/-), Fbln5 RGE/RGE mice were able to form intact elastic fibers and did not exhibit POP. However, treatment of mice with β-aminopropionitrile (BAPN), an inhibitor of matrix cross-linking enzymes, induced subclinical POP. Conversely, deletion of Mmp9 in Fbln5 -/-mice significantly attenuated POP by increasing elastic fiber density and improving collagen fibrils. Vaginal tissue samples from pre-and postmenopausal women with POP also displayed significantly increased levels of MMP-9. These results suggest that POP is an acquired disorder of extracellular matrix and that therapies targeting matrix proteases may be successful for preventing or ameliorating POP in women. IntroductionPelvic organ prolapse (POP) is characterized by abnormal protrusion of female pelvic organs involving the uterus, bladder, and vagina (reviewed in refs. 1-3). Epidemiologic studies indicate that (a) vaginal birth, aging, and increased body mass index are major risk factors for the development of POP and (b) more than 1 pathology may be involved to exhibit full anatomical loss of support. Although approximately 11% of women have surgery for POP or urinary incontinence in their lifetimes (4), to date, effective therapies to prevent progression of POP have not been established, thereby imposing profound social and financial burden to affected individuals (3).Despite a difference in anatomical position of pelvic organs relative to the body axis and pelvic floor, rodent models of POP have provided important tools to study underlying mechanisms of prolapse. In contrast to an observation that rectal prolapse is frequently associated with the presence of chronic inflammatory bowel disease (5), POP has been found in animals with defective ECM proteins, including fibulin-3, fibulin-5, and lysyl oxidaselike-1 (LOXL-1) (an enzyme that predominantly catalyzes crosslinking of elastin) (6-8). Interestingly, these proteins are abundantly expressed in the vaginal wall and involved in synthesis and assembly of elastic fibers. It is also known that uterosacral ligaments support the vaginal wall and that Hoxa11 is essential for formation of uterosacral ligaments in mice (9). Hoxa11-deficient mice exhibit increased mobility of the uterus; however,

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Role of Fibulin 3 in Aging‐Related Joint Changes and Osteoarthritis Pathogenesis in Human and Mouse Knee Cartilage

Hasegawa

Yonezawa

Taniguchi

et al. 2017

Arthritis & Rheumatology

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Objectives The EFEMP1 gene encoding fibulin-3 is specifically expressed in the superficial zone of articular cartilage. This study examined fibulin-3 expression patterns in joint aging and osteoarthritis (OA) and the role of fibulin-3 in OA pathogenesis. Methods Immunohistochemical analysis was performed on normal and OA human and mouse knee cartilage. Experimental OA was induced in wild type and fibulin-3−/− mice and OA severity was evaluated by histological scoring. To examine fibulin-3 function, chondrocyte monolayer cultures were transfected with siRNA for quantitative PCR and Western blot analyses. Bone marrow mesenchymal stem cells (MSC) were transduced with EFEMP1 lentivirus and analyzed for chondrogenesis markers. Results Fibulin-3 was specifically expressed in the SZ of normal cartilage in human and mouse knee joints and declined with aging. Both aging-related OA and experimental OA were significantly more severe in fibulin-3−/− mice compared with wild type mice. Fibulin-3 expression was high in undifferentiated MSC and decreased during chondrogenesis. Suppression of fibulin-3 by siRNA significantly increased SOX9, collagen II and aggrecan in articular chondrocytes, while overexpression of fibulin-3 inhibited chondrogenesis in MSC. Conclusion Fibulin-3 is specifically expressed in the SZ of articular cartilage and its expression is reduced in aging and OA. Fibulin-3 regulates differentiation of adult progenitor cells and its aging-related decline is an early event in OA pathogenesis. Preventing or restoring aging-associated loss of fibulin-3 in SZ chondrocytes has potential to delay or prevent onset of OA.

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Failure of Pelvic Organ Support in Mice Deficient In Fibulin-3

Cited by 75 publications

References 36 publications

Fibulin-5: two for the price of one maintaining pelvic support

Fibulin-5: two for the price of one maintaining pelvic support

Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans

Role of Fibulin 3 in Aging‐Related Joint Changes and Osteoarthritis Pathogenesis in Human and Mouse Knee Cartilage

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