Lysyl oxidase (protein-lysine 6-oxidase; EC 1.4.3.13 ) is an extracellular copper enzyme that initiates the crosslinking
of collagens and elastin by catalyzing oxidative deamination of the epsilon-amino group in certain lysine and
hydroxylysine residues of collagens and lysine residues of elastin.
NCBI Summary:
This gene encodes a member of the lysyl oxidase family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate a regulatory propeptide and the mature enzyme. The copper-dependent amine oxidase activity of this enzyme functions in the crosslinking of collagens and elastin, while the propeptide may play a role in tumor suppression. In addition, defects in this gene have been linked with predisposition to thoracic aortic aneurysms and dissections. [provided by RefSeq, Jul 2016]
General function
Enzyme, Oxidoreductase
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Cellular localization
Extracellular Matrix, Secreted
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Ovarian function
Follicle development
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Lysyl oxidase blockade ameliorates anovulation in polycystic ovary syndrome. Zhang C et al. (2018) Is overexpression of lysyl oxidase (LOX), an enzyme responsible for the cross-linking of collagens, a cause of anovulation in polycystic ovary syndrome (PCOS)? LOX overexpression was present in PCOS ovaries, due at least in part to interleukin-1β (IL-1β), and inhibition of LOX activity with β-aminopropionitrile (BAPN) ameliorated polycystic ovary morphology and anovulation. Aberrant ovarian extracellular matrix (ECM) remodeling and inflammation may contribute to the development of PCOS. It remains unknown whether proinflammatory IL-1β is a contributing factor for LOX overexpression in PCOS ovaries and whether inhibition of LOX can improve PCOS conditions. LOX and IL-1β abundance in the granulosa cells and follicular fluid was compared between non-PCOS (n = 30) and PCOS (n = 39) patients. The effect and mechanism of IL-1β on LOX expression was examined in cultured primary human granulosa cells. The improvements in PCOS conditions by LOX inhibition with BAPN was investigated in a dehydroepiandrosterone (DHEA)-induced PCOS rat model. The abundance of LOX and IL-1β was measured with quantitative real-time polymerase chain reaction (qRT-PCR), LOX activity assays and enzyme-linked immunosorbent assays (ELISA), respectively. The effect of IL-1β on LOX expression was examined in the presence or absence of inhibitors for signaling molecules and small interfering RNA-mediated knockdown of the putative transcription factor. Chromatin immunoprecipitation assays were conducted to further identify the responsible transcription factor. The role of LOX in ovulation was investigated in a DHEA-induced PCOS rat model with administration of the LOX inhibitor BAPN. The numbers of retrieved total oocytes and MII oocytes were recorded upon ovarian stimulation. Increased abundance of LOX (P < 0.05) and IL-1β (P < 0.05) was observed in the granulosa cells and follicular fluid in PCOS patients. IL-1β increased LOX expression via activation of ERK1/2 and JNK and subsequent activation of the transcription factor c-Jun. Inhibition of LOX with BAPN ameliorated irregular estrous cyclicity (P < 0.05), polycystic ovary morphology and anovulation (P < 0.05) in PCOS rats, but appeared to be ineffective in the improvement of oocyte quality. N/A. Ovarian tissue-directed specific inhibition of LOX in combination with oocyte quality-improving drugs may be more effective in the treatment of PCOS. Inflammation of the ovary is a contributing factor for the aberrant expression of LOX in the PCOS ovary, and inhibition of LOX together with anti-inflammatory therapy may improve the core features of PCOS. This work was supported by National Key R & D Program of China (2017YFC1001403) and Doctorial Innovation Fund of Shanghai Jiao Tong University School of Medicine (BXJ201718). The authors declare no competing financial interests.//////////////////
Activin A-induced increase in LOX activity in human granulosa-lutein cells is mediated by CTGF. Chang HM et al. (2016) Lysyl oxidase (LOX) is the key enzyme involved in the crosslinking of collagen and elastin that is essential for the formation of extracellular matrix (ECM). LOX-mediated ECM remodeling plays a critical role in follicle development, oocyte maturation and corpus luteum formation. To date, the regulation of LOX in human ovary has never been elucidated. Activin A and its functional receptors are highly expressed in ovarian follicles from an early developmental stage. They locally regulate follicle progression. The aim of this study was to investigate the effects of activin A on the expression of LOX and its extracellular enzyme activity in primary and immortalized human granulosa-lutein cells obtained from patients undergoing an in vitro fertilization procedure. We demonstrated that activin A significantly upregulated the expression of connective tissue growth factor (CTGF) and LOX via an activin/TGF-β type I receptor mediated-signaling pathway. Using a target depletion small interfering RNA knockdown approach, we further confirmed that the upregulation of CTGF expression resulted in an activin-A-induced increases in LOX expression and activity. These findings may provide insight into the mechanisms by which intrafollicular growth factors regulate the expression of LOX for ECM formation and tissue remodeling in the human ovary.//////////////////
Lysyl oxidase interacts with AGEs signaling to modulate collagen synthesis in polycystic ovarian tissue. Papachroni KK et al. Abstract Connective tissue components, collagen types I, III and IV surrounding the ovarian follicles undergo drastic changes during ovulation. Abnormal collagen synthesis and increased volume and density of ovarian stroma characterize the polycystic ovary syndrome (PCOS). During the ovulatory process, collagen synthesis is regulated by prolyl hydroxylase and lysyl oxidase (LOX) activity in ovarian follicles. LOX catalyzes collagen and elastin cross-linking and plays essential role in coordinating the control of ovarian extracellular matrix (ECM) during follicular development. We have recently shown accumulation of advanced glycation end products (AGEs), molecules that stimulate ECM production and abnormal collagen cross-linking, in ovarian tissue. However, the possible link between LOX and AGEs-induced signaling in collagen production and stroma formation in ovarian tissue from PCOS, remains elusive. The present study investigates the hypothesis of AGEs signaling pathway interaction with LOX gene activity in polycystic ovarian (PCO) tissue. We show an increased distribution and co-localization of LOX, collagen type IV and AGE molecules in the PCO tissue compared to control, as well as augmented expression of AGE signaling mediators/effectors, phospho(p)-ERK, phospho(p)-c-Jun and nuclear factor kappaB (NF-kappaB) in pathological tissue. Moreover, we demonstrate binding of AGE-induced transcription factors, NF-kappaB and activator protein-1 (AP-1) on LOX promoter, indicating a possible involvement of AGEs in LOX gene regulation which may account for the documented increase in LOX mRNA and protein levels compared to control. These findings suggest that deposition of excess collagen in PCO tissue that induces cystogenesis may, in part, be due to AGE-mediated stimulation of LOX activity.
T Endo HH, et al reported lysyl Oxidase and MMP-2 Expression in Dehydroepiandrosterone-Induced Polycystic Ovary in Rats.
Polycystic ovary syndrome (PCOS) is characterized by cystogenesis; however, the cause of this cystogenesis is unknown. At ovulation, preovulatory collagenolytic activities in the ovarian follicles increase and various proteinases are needed to degrade the tissues surrounding the follicles. To clarify the roles of enzymes in collagen degradation of the follicular wall of polycystic ovary (PCO) in relation to the cystogenesis, the authors examined expression of lysyl oxidase (LOX), which initiates cross-link formation of the collagen and elastin in the extracellular matrix, and expression of matrix metalloproteinases (MMPs) in ovaries of model rats with PCO induced by dehydroepiandrosterone (DHEA) compared with MMP expression in control rats. DHEA treatment increased LOX mRNA expression to more than three times the control value . MMP-2 mRNA expression in control rats was threefold greater than that in the DHEA-induced group .
Bone morphogenetic protein 2 increases lysyl oxidase activity via up-regulation of snail in human granulosa-lutein cells. Bai L et al. (2018) Lysyl oxidase (LOX) is a copper-dependent enzyme that maintains and stabilizes the extracellular matrix (ECM) by catalyzing the cross-linking of elastin and collagen. ECM within the ovarian follicle plays a crucial role in regulating follicular development and oocyte maturation. Bone morphogenetic protein 2 (BMP2) belongs to the BMP subfamily that has been shown to be involved in the process of ovarian folliculogenesis and luteal formation. To date, whether BMP2 regulates the activity of LOX during human follicular development remains to be elucidated. The aim of this study was to investigate the effect of BMP2 on the regulation of LOX expression and activity in human granulosa-lutein cells (hGL) and the underlying mechanisms. Using both primary and immortalized (SVOG cells) hGL cells, we demonstrated that BMP2 up-regulated the expression and activity of LOX and hence decreased the soluble collagens in cultured medium in hGL cells. Additionally, the mRNA and protein levels of two transcriptional factors, SNAIL and SLUG, were increased following cell exposure to BMP2. Knockdown of SNAIL, but not SLUG partially reversed BMP2-induced increases in LOX expression and activity. The BMP2-induced up-regulation of SNAIL expression was abolished by the pre-treatment with two BMP type I receptor inhibitors, dorsomorphin and DMH-1, but not SB431542. Moreover, knockdown of SMAD4 completely abolished BMP2-induced up-regulation of SNAIL expression and the subsequent increases in LOX expression and activity. Our results suggest that BMP2 increases LOX expression and activity via the up-regulation of SNAIL in hGL cells. These findings may provide insights into the functional role of BMP2 in the regulation of ECM formation during folliculogenesis.//////////////////
Connective tissue growth factor mediates growth differentiation factor 8-induced increase of lysyl oxidase activity in human granulosa-lutein cells. Chang HM et al. (2016) Lysyl oxidase (LOX) is an essential enzyme for the stabilization of the extracellular matrix (ECM) and the subsequent follicle and oocyte maturation. Currently, there is limited information pertaining to the regulation of LOX activity in human ovarian tissue. Growth differentiation factor 8 (GDF8) is a unique member of the transforming growth factor-β superfamily that is expressed in human granulosa cells and has important roles in regulating a variety of ovarian functions. The aim of the present study was to investigate the effects of GDF8 on the regulation of LOX expression and activity in human granulosa cells and to examine the underlying molecular determinants. An established immortalized human granulosa cell line (SVOG) and primary granulosa-lutein cells were used as study models. Using dual inhibition approaches (TGF-β type I inhibitor SB505124 and small interfering RNAs) and ChIP analyses, we have demonstrated that GDF8 up-regulated the expression of connective tissue growth factor (CTGF) through the activin receptor-like kinase 5-mediated SMAD2/3-SMAD4 signaling pathways. In addition, the increase in CTGF expression contributed to the GDF8-induced increase in LOX expression and activity. Our findings suggest that GDF8 and CTGF may play critical roles in the regulation of ECM formation in human granulosa cells.//////////////////
Increases in ORG DNA microarray.///////////TGF-β1 increases lysyl oxidase by reducing miR-29a in human granulosa-lutein cells. Fang Y et al. (2016) Lysyl oxidase (LOX), a key enzyme in the formation and stabilization of the extracellular matrix, is expressed in granulosa cells and plays a critical role in the regulation of granulosa cell differentiation, oocyte maturation and ovulation. To date, the regulation of LOX expression in human granulosa cells remains largely unknown. In the present study, using primary and immortalized human granulosa-lutein cells, we demonstrated that transforming growth factor (TGF)-β1 up-regulated LOX expression and down-regulated microRNA-29a (miR-29a) expression via a TGF-β type I receptor-mediated signaling pathway. Additionally, we showed that miR-29a down-regulated the expression of LOX in both types of cells. Furthermore, the down-regulation of miR-29a contributed to the TGF-β1-induced increase in LOX expression because the inhibition of miR-29a with a miR-29a inhibitor not only reversed the miR-29a-induced down-regulation of LOX but also enhanced the TGF-β1-induced up-regulation of LOX. Our findings suggest that TGF-β1 and miR-29a may play essential roles in the regulation of extracellular matrix remodeling during the periovulatory phase.//////////////////
Slee RB,et al 2001 reported differentiation-dependent expression of connective tissue
growth factor and lysyl oxidase messenger ribonucleic acids in
rat granulosa cells.
They carried out differential display RT-PCR (DDRT-PCR) on
RNA from gonadotropin-stimulated rat granulosa cells (GC). GC from preantral
and early antral follicles in immature rat ovaries were cultured in serum-free
medium containing no hormone (control), recombinant human FSH (10 ng/ml),
5alpha-dihydrotestosterone (DHT; 10(-6) M), or FSH plus DHT. Total cellular
RNA was extracted from cells at 6, 12, 24, and 48 h of treatment for DDRT-PCR
analysis. Six distinct complementary DNA clones were obtained that
reproduced the DDRT-PCR profile on a Northern blot of the corresponding RNA
samples. Two of these clones detected transcripts that were strongly
down-regulated by FSH. One corresponded to connective tissue growth factor
(CTGF), a cysteine-rich secreted protein related to platelet-derived growth factor that is implicated in mitogenesis and angiogenesis, and a second was identical to lysyl oxidase (LO), a key participant in extracellular matrix deposition. In detailed expression studies, Northern analysis revealed a single, approximately 2.5-kb CTGF transcript maximally suppressed within 3 h of exposure to FSH with
or without DHT and two LO transcripts ( approximately 3.8 and approximately 5.2 kb) maximally suppressed at 6 h. DHT alone did not affect CTGF mRNA, but strongly enhanced LO mRNA relative to the control value. In vivo, CTGF and LO transcripts were significantly suppressed in GC 48 h after equine CG injection (10
IU, ip) compared with untreated controls and were further reduced 12 h after
administration of additional 10 IU hCG to induce luteinization. In situ
hybridization confirmed GC in preantral/early antral follicles as principal sites of
CTGF and LO mRNA expression.
Ovarian localization
Oocyte, Granulosa, Follicular Fluid
Comment
Christopher R. Harlow, et al 2003 reported the Lysyl Oxidase Gene Expression and Enzyme Activity in the Rat Ovary and Regulation by Follicle-Stimulating Hormone, Androgen, and Transforming Growth Factor-?Superfamily Members in Vitro .
Lysyl oxidase (LOX) catalyzes the final enzymatic reaction required for cross-linking of collagen and elastin fibers and therefore has a crucial role in regulating the formation and maintenance of extracellular matrix in the ovary. LOX mRNA is abundantly expressed in rat granulosa cells. To examine how regulation of LOX in the ovary might influence follicular development, the authors studied LOX mRNA expression and enzyme activity in rat granulosa cells from late preantral/early antral follicles in vitro. FSH dose dependently inhibited LOX mRNA and enzyme activity (50% reduction at 10 ng/ml) in vitro, and FSH action was mimicked by 8-bromo-cAMP, suggesting FSH action via elevation of cAMP. Dihydrotestosterone alone enhanced LOX mRNA and enzyme activity, but potentiated the effect of FSH, causing a further reduction. TGF? alone dose dependently enhanced LOX mRNA (5-fold increase at 10 ng/ml) and activity (1.5-fold increase). FSH dose dependently inhibited the increase in LOX mRNA and activity caused by TGF? (by up to 84% and 80%, respectively). Growth differentiation factor-9 (GDF-9) and activin A, at the same concentration as TGF? (10 ng/ml), stimulated LOX mRNA and activity within 6 h, although overall expression was higher at 48 h. All three factors when combined with FSH further reduced both mRNA and enzyme activity (by up to 60%) compared with FSH alone. These findings indicate control of LOX at endocrine, paracrine, and autocrine levels within the ovary and suggest coordinated regulation of ovarian extracellular matrix during follicular development, with FSH determining whether local factors act as stimulators or inhibitors of LOX.
Follicle stages
Antral, Preovulatory
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PMID: 27530347
Genomewide discovery and classification of candidate ovarian fertility genes in the mouse. Gallardo TD et al. Female infertility syndromes are among the most prevalent chronic health disorders in women, but their genetic basis remains unknown because of uncertainty regarding the number and identity of ovarian factors controlling the assembly, preservation, and maturation of ovarian follicles. To systematically discover ovarian fertility genes en masse, we employed a mouse model (Foxo3) in which follicles are assembled normally but then undergo synchronous activation. We developed a microarray-based approach for the systematic discovery of tissue-specific genes and, by applying it to Foxo3 ovaries and other samples, defined a surprisingly large set of ovarian factors (n = 348, approximately 1% of the mouse genome). This set included the vast majority of known ovarian factors, 44% of which when mutated produce female sterility phenotypes, but most were novel. Comparative profiling of other tissues, including microdissected oocytes and somatic cells, revealed distinct gene classes and provided new insights into oogenesis and ovarian function, demonstrating the utility of our approach for tissue-specific gene discovery. This study will thus facilitate comprehensive analyses of follicle development, ovarian function, and female infertility. This is an oocyte- and cumulus-specific gene.