Loxl2 and Loxl3 Paralogues Play Redundant Roles during Mouse Development.

Lysyl oxidase-like 2 (LOXL2) and 3 (LOXL3) are members of the lysyl oxidase family of enzymes involved in the maturation of the extracellular matrix. Both enzymes share a highly conserved catalytic domain, but it is unclear whether they perform redundant functions in vivo. In this study, we show that mice lacking Loxl3 exhibit perinatal lethality and abnormal skeletal development. Additionally, analysis of the genotype of embryos carrying double knockout of Loxl2 and Loxl3 genes suggests that both enzymes have overlapping functions during mouse development. Furthermore, we also show that ubiquitous expression of Loxl2 suppresses the lethality associated with Loxl3 knockout mice.

Correlation of Matrisome-Associatted Gene Expressions with LOX Family Members in Astrocytomas Stratified by IDH Mutation Status.

Tumor cell infiltrative ability into surrounding brain tissue is a characteristic of diffusely infiltrative astrocytoma and is strongly associated with extracellular matrix (ECM) stiffness. Collagens are the most abundant ECM scaffolding proteins and contribute to matrix organization and stiffness. LOX family members, copper-dependent amine oxidases, participate in the collagen and elastin crosslinking that determine ECM tensile strength. Common IDH mutations in lower-grade gliomas (LGG) impact prognosis and have been associated with ECM stiffness. We analyzed the expression levels of LOX family members and matrisome-associated genes in astrocytoma stratified by malignancy grade and IDH mutation status. A progressive increase in expression of all five LOX family members according to malignancy grade was found. LOX, LOXL1, and LOXL3 expression correlated with matrisome gene expressions. LOXL1 correlations were detected in LGG with IDH mutation (IDHmut), LOXL3 correlations in LGG with IDH wild type (IDHwt) and strong LOX correlations in glioblastoma (GBM) were found. These increasing correlations may explain the increment of ECM stiffness and tumor aggressiveness from LGG-IDHmut and LGG-IDHwt through to GBM. The expression of the mechanosensitive transcription factor, ß-catenin, also increased with malignancy grade and was correlated with LOXL1 and LOXL3 expression, suggesting involvement of this factor in the outside-in signaling pathway.

LOXL3 Silencing Affected Cell Adhesion and Invasion in U87MG Glioma Cells.

Lysyl oxidase-like 3 (LOXL3), belonging to the lysyl oxidase family, is responsible for the crosslinking in collagen or elastin. The cellular localization of LOXL3 is in the extracellular space by reason of its canonical function. In tumors, the presence of LOXL3 has been associated with genomic stability, cell proliferation, and metastasis. In silico analysis has shown that glioblastoma was among tumors with the highest LOXL3 expression levels. LOXL3 silencing of U87MG cells by siRNA led to the spreading of the tumor cell surface, and the transcriptome analysis of these cells revealed an upregulation of genes coding for extracellular matrix, cell adhesion, and cytoskeleton components, convergent to an increase in cell adhesion and a decrease in cell invasion observed in functional assays. Significant correlations of LOXL3 expression with genes coding for tubulins were observed in the mesenchymal subtype in the TCGA RNA-seq dataset of glioblastoma (GBM). Conversely, genes involved in endocytosis and lysosome formation, along with MAPK-binding proteins related to focal adhesion turnover, were downregulated, which may corroborate the observed decrease in cell viability and increase in the rate of cell death. Invasiveness is a major determinant of the recurrence and poor outcome of GBM patients, and downregulation of LOXL3 may contribute to halting the tumor cell invasion.

The lysyl oxidase like 2/3 enzymatic inhibitor, PXS-5153A, reduces crosslinks and ameliorates fibrosis.

Fibrosis is characterized by the excessive deposition of extracellular matrix and crosslinked proteins, in particular collagen and elastin, leading to tissue stiffening and disrupted organ function. Lysyl oxidases are key players during this process, as they initiate collagen crosslinking through the oxidation of the ε-amino group of lysine or hydroxylysine on collagen side-chains, which subsequently dimerize to form immature, or trimerize to form mature, collagen crosslinks. The role of LOXL2 in fibrosis and cancer is well documented, however the specific enzymatic function of LOXL2 and LOXL3 during disease is less clear. Herein, we describe the development of PXS-5153A, a novel mechanism based, fast-acting, dual LOXL2/LOXL3 inhibitor, which was used to interrogate the role of these enzymes in models of collagen crosslinking and fibrosis. PXS-5153A dose-dependently reduced LOXL2-mediated collagen oxidation and collagen crosslinking in vitro. In two liver fibrosis models, carbon tetrachloride or streptozotocin/high fat diet-induced, PXS-5153A reduced disease severity and improved liver function by diminishing collagen content and collagen crosslinks. In myocardial infarction, PXS-5153A improved cardiac output. Taken together these results demonstrate that, due to their crucial role in collagen crosslinking, inhibition of the enzymatic activities of LOXL2/LOXL3 represents an innovative therapeutic approach for the treatment of fibrosis.

LOXL3 novel mutation causing a rare form of autosomal recessive Stickler syndrome.

Stickler syndrome is a collagenopathy that is typically inherited as autosomal dominant disease caused by monoallelic mutations in COL2A1, COL11A2, and COL11A1. Rarely, biallelic mutations in COL9A1, COL9A2, and COL9A3 cause an autosomal recessive Stickler syndrome. One previous report described two siblings with Stickler syndrome and a homozygous mutation in LOXL3, suggesting that biallelic mutations in LOXL3 can also cause autosomal recessive Stickler syndrome. LOXL3 is a member of the lysyl oxidase family of genes which encode enzymes oxidizing the side chain of peptidyl lysine permitting the covalent crosslinking of collagen and elastin chains. Therefore, LOXL3 deficiency is expected to result in collagen defect. Furthermore, Loxl3 deficient mouse model demonstrated features overlapping with Stickler syndrome. In this report, we describe a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. This report not only supports that biallelic LOXL3 mutations cause autosomal recessive Stickler syndrome, but also further delineates the phenotype associated with LOXL3 mutations. In addition, the family described here shows an interesting example for pseudodominance, which can be observed in recessive diseases when one parent is affected and the other is heterozygous carrier.

LOXL3 Function Beyond Amino Oxidase and Role in Pathologies, Including Cancer.

Lysyl oxidase like 3 (LOXL3) is a copper-dependent amine oxidase responsible for the crosslinking of collagen and elastin in the extracellular matrix. LOXL3 belongs to a family including other members: LOX, LOXL1, LOXL2, and LOXL4. Autosomal recessive mutations are rare and described in patients with Stickler syndrome, early-onset myopia and non-syndromic cleft palate. Along with an essential function in embryonic development, multiple biological functions have been attributed to LOXL3 in various pathologies related to amino oxidase activity. Additionally, various novel roles have been described for LOXL3, such as the oxidation of fibronectin in myotendinous junction formation, and of deacetylation and deacetylimination activities of STAT3 to control of inflammatory response. In tumors, three distinct roles were described: (1) LOXL3 interacts with SNAIL and contributes to proliferation and metastasis by inducing epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma cells; (2) LOXL3 is localized predominantly in the nucleus associated with invasion and poor gastric cancer prognosis; (3) LOXL3 interacts with proteins involved in DNA stability and mitosis completion, contributing to melanoma progression and sustained proliferation. Here we review the structure, function and activity of LOXL3 in normal and pathological conditions and discuss the potential of LOXL3 as a therapeutic target in various diseases.

Leptin promotes apoptosis and inhibits autophagy of chondrocytes through upregulating lysyl oxidase-like 3 during osteoarthritis pathogenesis.

OBJECTIVE: Leptin has been found highly expressed in human osteoarthritis. We aimed to explore the possible effects and mechanisms of leptin on the apoptosis and autophagy of chondrocytes during osteoarthritis pathogenesis. METHODS: Gene expression profile from osteoarthritis affected and preserved cartilage were downloaded from NCBI's Gene Expression Omnibus database (GSE57218). Lysyl oxidase-like 3 (LOXL3) mRNA expression in cartilage tissues and leptin concentration in joint synovial fluid (SF) was measured in samples from 45 osteoarthritis patients and 25 healthy donors by real-time PCR and radioimmunoassay, respectively. Rat osteoarthritis model was induced by anterior cruciate ligament transection (ACLT). The expression of apoptosis regulators and autophagy markers were detected by Western blot. Cell survival and cell apoptosis were identified by CCK-8 and flow cytometry, respectively. RESULTS: Re-analysis on GSE57218 indicated that LOXL3 mRNA was upregulated in osteoarthritis affected cartilage. LOXL3 mRNA was upregulated in osteoarthritis patients, which was positively correlated with SF leptin concentration. Similar results were obtained in rat osteoarthritis model. Moreover, ACLT surgery led to a significant increase in the protein levels of cleaved caspase 3, and a notable decrease in the protein levels of Bcl-2, LC3 II/LC3 I and Beclin1. Silencing of LOXL3 in ACLT and leptin treated primary chondrocytes significantly inhibited cell apoptosis, and promoted cell proliferation and autophagy. Moreover, overexpression of LOXL3 remarkably inhibited autophagy of chondrocytes via activating mTORC1. CONCLUSIONS: LOXL3, a downstream of leptin, stimulated the apoptosis, but inhibited the autophagy of chondrocytes. LOXL3 is a potential therapy target for osteoarthritis.

Expression of LOXL3, NES, and SNAI1 in Melanoma Genesis and Progression.

Melanoma is the most severe type of skin cancer and among the most malignant neoplasms in humans. With the growing incidence of melanoma, increased numbers of therapeutic options, and the potential to target specific proteins, understanding the basic mechanisms underlying the disease's progression and resistance to treatment has never been more important. LOXL3, SNAI1, and NES are key factors in melanoma genesis, regulating tumor growth, metastasis, and cellular differentiation. In our study, we explored the potential role of LOXL3, SNAI1, and NES in melanoma progression and metastasis among patients with dysplastic nevi, melanoma in situ, and BRAF+ and BRAF- metastatic melanoma, using immunofluorescence and qPCR analysis. Our results reveal a significant increase in LOXL3 expression and the highest NES expression in BRAF+ melanoma compared to BRAF-, dysplastic nevi, and melanoma in situ. As for SNAI1, the highest expression was observed in the metastatic melanoma group, without significant differences among groups. We found co-expression of LOXL3 and SNAI1 in the perinuclear area of all investigated subgroups and NES and SNAI1 co-expression in melanoma cells. These findings suggest a codependence or collaboration between these markers in melanoma EMT, suggesting new potential therapeutic interventions to block the EMT cascade that could significantly affect survival in many melanoma patients.

Novel LOXL3-associated stickler syndrome-like phenotype: a case report.

PURPOSE: To report the case of a young boy with early onset high myopia (eoHM), foveal hypoplasia and skeletal dysplasia due to a homozygous LOXL3 pathogenic variant. Atypically, this was from a paternal uniparental isodisomy (UPiD) of chromosome 2. CLINICAL CASE: Four-year-old boy with several months history of holding items close to his face was found to have reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed spondylo-epi-metaphyseal dysplasia. Whole-exome sequencing (WES) revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2. CONCLUSION: To our knowledge, this is the first reported case of LOXL3-associated eoHM, foveal hypoplasia and mild skeletal dysplasia due to the rare phenomenon of paternal UPiD of chromosome 2. This case further delineates the phenotype associated with LOXL3 pathogenic variants and supports truncating LOXL3 pathogenic variants being associated with a phenotypic spectrum; from isolated eoHM through to a Stickler syndrome-like phenotype.

LOXL3 Silencing Hampers the Metastasis and Angiogenesis of Gastric Cancer Cells Dependent on Ferroptosis Activation.

Gastric cancer (GC) remains a major unmet clinical problem accountable for considerable incidence and fatality rate. Lysyl oxidase-like 3 (LOXL3) has been recognized to be overexpressed in GC. Our work was meant to disclose the significance of LOXL3 in the advancement of GC and the likely action mechanism. LOXL3 expression in GC tissues and its correlation with the outcome of GC patients were investigated through bioinformatics tools. RT-qPCR and western blotting inspected LOXL3 expression in GC cells. CCK-8 method, EDU, as well as colony formation assays assayed cell proliferation. The capacities of cells to migrate and invade were appraised by wound healing and transwell assays, severally. Tube formation assay and ELISA measured angiogenesis. TBARS, C11 BODIPY staining, and FerroOrange estimated ferroptosis. Western blotting examined the expression of proteins implicated in metastasis and ferroptosis. The up-regulation of LOXL3 expression was noticed in GC tissues and cells, which was also associated with the poor outcome of GC patients. When LOXL3 was underexpressed, the proliferation, migration, invasion, epithelial-mesenchymal transition, and angiogenesis of GC cells were all halted. In addition, LOXL3 deletion resulted in the activation of ferroptosis in GC cells, and ferrostatin-1 (Fer-1), the specific ferroptosis inhibitor, compensated the suppressive role of LOXL3 down-regulation in the proliferation, metastasis, and angiogenesis of GC cells in vitro. All in all, knockdown of LOXL3 may serve an activator of ferroptosis to obstruct the aggressive process of GC.

LOXL3 Inhibits Autophagy of Chondrocytes by Activating Rheb in Osteoarthritis.

OBJECTIVE: This study aimed to investigate the potential mechanisms by which lysyl oxidase like 3 (LOXL3) affects the autophagy in chondrocytes in osteoarthritis (OA), specifically through the activation of mammalian target of rapamycin complex 1 (mTORC1). METHODS: To establish an OA model, rats underwent anterior cruciate ligament transection (ACLT). Chondrocytes were isolated from cartilage tissues and cultured. Western blotting was performed to assess the expression of LOXL3, Rheb, phosphorylation of p70S6K (p-p70S6K, a downstream marker of mTORC1), and autophagy markers. The autophagy of chondrocytes was observed using an immunofluorescence assay. RESULTS: The expression levels of both LOXL3 and Rheb proteins were upregulated in chondrocytes isolated from the OA model cartilage, in comparison to those from the normal cartilage. The silencing of LOXL3 resulted in a decrease in the protein levels of Rheb and p-p70S6K, as well as an increase in the expression of autophagy-related proteins. Additionally, the effect of LOXL3 could be reversed through the silencing of Rheb. The results of the immunofluorescence assay confirmed the impact of LOXL3 and Rheb on chondrocyte autophagy. CONCLUSION: LOXL3 inhibits chondrocyte autophagy by activating the Rheb and mTORC1 signaling pathways.

LncRNA CFAR promotes cardiac fibrosis via the miR-449a-5p/LOXL3/mTOR axis.

Cardiac fibrosis is one of the crucial pathological factors in the heart, and various cardiac conditions associated with excessive fibrosis can eventually lead to heart failure. However, the exact molecular mechanism of cardiac fibrosis remains unclear. In the present study, we show that a novel lncRNA that we named cardiac fibrosis-associated regulator (CFAR) is a profibrotic factor in the heart. CFAR was upregulated in cardiac fibrosis and its knockdown attenuated the expression of fibrotic marker genes and the proliferation of cardiac fibroblasts, thereby ameliorating cardiac fibrosis. Moreover, CFAR acted as a ceRNA sponge for miR-449a-5p and derepressed the expression of LOXL3, which we experimentally established as a target gene of miR-449a-5p. In contrast to CFAR, miR-449a-5p was found to be significantly downregulated in cardiac fibrosis, and artificial knockdown of miR-449a-5p exacerbated fibrogenesis, whereas overexpression of miR-449a-5p impeded fibrogenesis. Furthermore, we found that LOXL3 mimicked the fibrotic factor TGF-ß1 to promote cardiac fibrosis by activating mTOR. Collectively, our study established CFAR as a new profibrotic factor acting through a novel miR-449a-5p/LOXL3/mTOR axis in the heart and therefore might be considered as a potential molecular target for the treatment of cardiac fibrosis and associated heart diseases.

Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival.

Malignant melanoma is a highly aggressive tumor causing most skin cancer-related deaths. Understanding the fundamental mechanisms responsible for melanoma progression and therapeutic evasion is still an unmet need for melanoma patients. Progression of skin melanoma and its dissemination to local or distant organs relies on phenotypic plasticity of melanoma cells, orchestrated by EMT-TFs and microphthalmia-associated TF (MITF). Recently, melanoma phenotypic switching has been proposed to uphold context-dependent intermediate cell states benefitting malignancy. LOXL3 (lysyl oxidase-like 3) promotes EMT and has a key role in human melanoma cell survival and maintenance of genomic integrity. To further understand the role of Loxl3 in melanoma, we generated a conditional Loxl3-knockout (KO) melanoma mouse model in the context of BrafV600E-activating mutation and Pten loss. Melanocyte-Loxl3 deletion increased melanoma latency, decreased tumor growth, and reduced lymph node metastatic dissemination. Complementary in vitro and in vivo studies in mouse melanoma cells confirmed Loxl3's contribution to melanoma progression and metastasis, in part by modulating phenotypic switching through Snail1 and Prrx1 EMT-TFs. Importantly, a novel LOXL3-SNAIL1-PRRX1 axis was identified in human melanoma, plausibly relevant to melanoma cellular plasticity. These data reinforced the value of LOXL3 as a therapeutic target in melanoma.

Autosomal Recessive Stickler Syndrome.

Stickler syndrome (SS) is a genetic disorder with manifestations in the eye, ear, joints, face and palate. Usually inherited in a dominant fashion due to heterozygous pathogenic variants in the collagen genes COL2A1 and COL11A1, it can rarely be inherited in a recessive fashion from variants in COL9A1, COL9A2, and COL9A3, COL11A1, as well as the non-collagen genes LRP2, LOXL3 and GZF1. We review the published cases of recessive SS, which comprise 40 patients from 23 families. Both homozygous and compound heterozygous pathogenic variants are found. High myopia is near-universal, and sensorineural hearing loss is very common in patients with variants in genes for type IX or XI collagen, although hearing appears spared in the LRP2 and LOXL3 patients and is variable in GZF1. Cleft palate is associated with type XI collagen variants, as well as the non-collagen genes, but is so far unreported with type IX collagen variants. Retinal detachment has occurred in 18% of all cases, and joint pain in 15%. However, the mean age of this cohort is 11 years old, so the lifetime incidence of both problems may be underestimated. This paper reinforces the importance of screening for SS in congenital sensorineural hearing loss, particularly when associated with myopia, and the need to warn patients and parents of the warning signs of retinal detachment, with regular ophthalmic review.

N6-methyladenosine reader YTHDF3 regulates melanoma metastasis via its 'executor'LOXL3.

BACKGROUND: A number of studies have demonstrated that N6-methyladenosine (m6A) plays a vital role in the pathological process of various tumours. Recently, it was found that m6A writers or erasers affect the tumourigenesis of melanoma. However, the relationship between m6A readers such as YTH domain family (YTHDF) proteins and melanoma was still elusive. METHODS: RT-qPCR, Western blot and immunohistochemistry were conducted to measure the expression level of YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) and lysyl oxidase-like 3 (LOXL3) in melanoma tissues and cells. The effects of YTHDF3 and LOXL3 on melanoma were verified in vitro and in vivo. Multi-omics analysis including RNA-seq, MeRIP-seq, RIP-seq and mass spectrometry analyses was performed to identify the target. The interaction between YTHDF3 and LOXL3 was verified by RT-PCR, Western blot, MeRIP-qPCR, RIP-qPCR and CRISPR-Cas13b-based epitranscriptome engineering. RESULTS: In this study, we found that m6A reader YTHDF3 could affect the metastasis of melanoma both in vitro and in vivo. The downstream targets of YTHDF3, such as LOXL3, phosphodiesterase 3A (PDE3A) and chromodomain helicase DNA-binding protein 7 (CHD7) were identified by means of RNA-seq, MeRIP-seq, RIP-seq and mass spectrometry analyses. Besides, RT-qPCR, Western blot, RIP-qPCR and MeRIP-qPCR were performed for subsequent validation. Among various targets of YTHDF3, LOXL3 was found to be the optimal target of YTHDF3. With the application of CRISPR-Cas13b-based epitranscriptome engineering, we further confirmed that the transcript of LOXL3 was captured and regulated by YTHDF3 via m6A binding sites. YTHDF3 augmented the protein expression of LOXL3 without affecting its mRNA level via the enrichment of eukaryotic translation initiation factor 3 subunit A (eIF3A) on the transcript of LOXL3. LOXL3 downregulation inhibited the metastatic ability of melanoma cells, and overexpression of LOXL3 ameliorated the inhibition of melanoma metastasis caused by YTHDF3 downregulation. CONCLUSIONS: The YTHDF3-LOXL3 axis could serve as a promising target to be interfered with to inhibit the metastasis of melanoma.

Identification of LOXL3-associating immune infiltration landscape and prognostic value in hepatocellular carcinoma.

In recent years, breakthroughs in the field of tumor immunotherapy with immune checkpoint inhibitors (ICIs) have made a therapeutic revolution, which has been shown to improve the prognosis of patients with hepatocellular carcinoma (HCC). Immune infiltrates represent a major component of tumor microenvironment (TME), and play an essential role in both tumor progression and therapeutic response. The major unmet challenge in tumor immunotherapy is exploring the intrinsic and extrinsic mechanisms of TME promoting the management of HCC. Lysyl oxidase like 3 (LOXL3) participates in the remodeling of extracellular matrix (ECM) and the cross-linking of collagen and elastic fibers. It has been reported that LOXL3 is associated with the development and tumorigenesis of multiple types of cancer. RNA sequencing data and corresponding clinical information were extracted from The Cancer Genome Atlas (TCGA) databases, then subjected to gene expression, tumor microenvironment, survival, enrichment analyses utilizing R packages. In this study, we first found that LOXL3 gene was upregulated in tumor tissues compared with the normal tissues. Furthermore, LOXL3 expression is positively correlated with the infiltration of multiple immune cells and the expression of immune checkpoint genes in HCC. Meanwhile, high LOXL3 expression predicted poor outcomes of the patients with HCC. Functional enrichment analysis suggested that LOXL3 was mainly linked to extracellular structure and matrix organization, cell-cell adhesion, and T cell activation. This is the first comprehensive study to indicate that LOXL3 is correlated with immune infiltrates and may serve as a novel biomarker predicting prognosis and immunotherapy in HCC.

Targeted Deletion of Loxl3 by Col2a1-Cre Leads to Progressive Hearing Loss.

Collagens are major constituents of the extracellular matrix (ECM) that play an essential role in the structure of the inner ear and provide elasticity and rigidity when the signals of sound are received and transformed into electrical signals. LOXL3 is a member of the lysyl oxidase (LOX) family that are copper-dependent amine oxidases, generating covalent cross-links to stabilize polymeric elastin and collagen fibers in the ECM. Biallelic missense variant of LOXL3 was found in Stickler syndrome with mild conductive hearing loss. However, available information regarding the specific roles of LOXL3 in auditory function is limited. In this study, we showed that the Col2a1-Cre-mediated ablation of Loxl3 in the inner ear can cause progressive hearing loss, degeneration of hair cells and secondary degeneration of spiral ganglion neurons. The abnormal distribution of type II collagen in the spiral ligament and increased inflammatory responses were also found in Col2a1-Loxl3-/- mice. Amino oxidase activity exerts an effect on collagen; thus, Loxl3 deficiency was expected to result in the instability of collagen in the spiral ligament and the basilar membrane, which may interfere with the mechanical properties of the organ of Corti and induce the inflammatory responses that are responsible for the hearing loss. Overall, our findings suggest that Loxl3 may play an essential role in maintaining hearing function.

Implications of lysyl oxidase-like protein 3 expression in the periodontium of diabetic rats

Abstract Objectives Diabetes has been strongly associated with periodontal diseases. The periodontal ligament (PDL) has an abundant extracellular matrix (ECM). Lysyl oxidases (LOXs) are closely associated with various diseases caused by abnormal ECM functions, however, the role of LOXs in periodontal diseases induced by diabetes remains unclear. Methodology In this study, 8-week-old Zucker diabetic fatty rats were used to establish a type 2 diabetes mellitus (T2DM) model. After 9 and 16 weeks, hematoxylin and eosin (H&E), Masson's trichrome, and immunohistochemical staining were performed. Results After 9 weeks, loose collagen fibers were found in the interradicular area of the diabetic group, in opposition to the control group. There were no significant differences in LOX expression between the diabetic and control groups (p>0.05). However, after 16 weeks, the diabetic group presented a disordered arrangement of the PDL, showing decreased collagen content and significantly increased lysyl oxidase-like protein 3 (LOXL3) expression when compared with the control group (p<0.05). This suggests that LOXL3 plays a significant role in periodontal histopathological changes in diabetic rats. Conclusion Our study showed elevated LOXL3 expression in the PDL of diabetic rats after 16 weeks, suggesting that LOXL3 may be involved in the occurrence and development of periodontal histopathological changes in diabetic rats. LOXL3 could be further used as an indicator for the early diagnosis of diabetic periodontitis in T2DM patients in clinical settings.