Roles for B[a]P and FICZ in subchondral bone metabolism and experimental temporomandibular joint osteoarthritis via the AhR/Cyp1a1 signaling axis.
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ABSTRACT:
SUBMITTER: Yoshikawa Y
PROVIDER: S-EPMC8295293 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ever since the 1970s, when profound immunosuppression caused by exogenous dioxin-like compounds was first observed, the involvement of the aryl hydrocarbon receptor (AHR) in immunomodulation has been the focus of considerable research interest. Today it is established that activation of this receptor by its high-affinity endogenous ligand, 6-formylindolo[3,2-b]carbazole (FICZ), plays important physiological roles in maintaining epithelial barriers. In the gut lumen, the small amounts of FICZ that are produced from L-tryptophan by microbes are normally degraded rapidly by the inducible cytochrome P4501A1 (CYP1A1) enzyme. This review describes how when the metabolic clearance of FICZ is attenuated by inhibition of CYP1A1, this compound passes through the intestinal epithelium to immune cells in the lamina propria. FICZ, the level of which is thus modulated by this autoregulatory loop involving FICZ itself, the AHR and CYP1A1, plays a central role in maintaining gut homeostasis by potently up-regulating the expression of interleukin 22 (IL-22) by group 3 innate lymphoid cells (ILC3s). IL-22 stimulates various epithelial cells to produce antimicrobial peptides and mucus, thereby both strengthening the epithelial barrier against pathogenic microbes and promoting colonization by beneficial bacteria. Dietary phytochemicals stimulate this process by inhibiting CYP1A1 and causing changes in the composition of the intestinal microbiota. The activity of CYP1A1 can be increased by other microbial products, including the short-chain fatty acids, thereby accelerating clearance of FICZ. In particular, butyrate enhances both the level of the AHR and CYP1A1 activity by stimulating histone acetylation, a process involved in the daily cycle of the FICZ/AHR/CYP1A1 feedback loop. It is now of key interest to examine the potential involvement of FICZ, a major physiological activator of the AHR, in inflammatory disorders and autoimmunity.
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Project description:Increased subchondral trabecular bone turnover due to imbalanced bone-resorbing and bone-forming activities is a hallmark of osteoarthritis (OA). Wnt5a/Ror2 signaling, which can derive from bone marrow stromal cells (BMSCs), takes a role in modulating osteoblast and osteoclast formation. We showed previously that experimentally unilateral anterior crossbites (UACs) elicited OA-like lesions in mice temporomandibular joints (TMJs), displaying as subchondral trabecular bone loss. Herein, we tested the role of BMSC-derived Wnt5a/Ror2 signaling in regulating osteoclast precursor migration and differentiation in this process. The data confirmed the decreased bone mass, increased tartrate-resistant acid phosphatase (TRAP)-positive cell number, and enhanced osteoclast activity in TMJ subchondral trabecular bone of UAC-treated rats. Interestingly, the osteoblast activity in the tissue of TMJ subchondral trabecular bone of these UAC-treated rats was also enhanced, displaying as upregulated expressions of osteoblast markers and increased proliferation, migration, and differentiation capabilities of the locally isolated BMSCs. These BMSCs showed an increased CXCL12 protein expression level and upregulated messenger RNA expressions of Rankl, Wnt5a, and Ror2. Ex vivo data showed that their capacities of inducing migration and differentiation of osteoclast precursors were enhanced, and these enhanced capabilities were restrained after blocking their Ror2 signaling using small interfering RNA (siRNA) assays. Reducing Ror2 expression in the BMSC cell line by siRNA or blocking the downstream signalings with specific inhibitors also demonstrated a suppression of the capacity of the BMSC cell line to promote Wnt5a-dependent migration (including SP600125 and cyclosporine A) and differentiation (cyclosporine A only) of osteoclast precursors. These findings support the idea that Wnt5a/Ror2 signaling in TMJ subchondral BMSCs enhanced by UAC promoted BMSCs to increase Cxcl12 and Rankl expression, in which JNK and/or Ca(2+)/NFAT pathways were involved and therefore were engaged in enhancing the migration and differentiation of osteoclast precursors, leading to increased osteoclast activity and an overall TMJ subchondral trabecular bone loss in the UAC-treated rats.
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Project description:The present study tested whether activation of the sympathetic tone by aberrant joint loading elicits abnormal subchondral bone remodeling in temporomandibular joint (TMJ) osteoarthritis. Abnormal dental occlusion was created in experimental rats, which were then intraperitoneally injected by saline, propranolol or isoproterenol. The norepinephrine contents, distribution of sympathetic nerve fibers, expression of ?-adrenergic receptors (?-ARs) and remodeling parameters in the condylar subchondral bone were investigated. Mesenchymal stem cells (MSCs) from condylar subchondral bones were harvested for comparison of their ?-ARs, pro-osteoclastic gene expressions and pro-osteoclastic function. Increases in norepinephrine level, sympathetic nerve fiber distribution and ?2-AR expression were observed in the condylar subchondral bone of experimental rats, together with subchondral bone loss and increased osteoclast activity. ?-antagonist (propranolol) suppressed subchondral bone loss and osteoclast hyperfunction while ?-agonist (isoproterenol) exacerbated those responses. MSCs from experimental condylar subchondral bone expressed higher levels of ?2-AR and RANKL; norepinephrine stimulation further increased their RANKL expression and pro-osteoclastic function. These effects were blocked by inhibition of ?2-AR or the PKA pathway. RANKL expression by MSCs decreased after propranolol administration and increased after isoproterenol administration. It is concluded that ?2-AR signal-mediated subchondral bone loss in TMJ osteoarthritisis associated with increased RANKL secretion by MSCs.
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Project description:BackgroundTemporomandibular joint osteoarthritis (TMJOA) is characterized by abnormal subchondral bone remodeling and cartilage degeneration. As a non-invasive biophysical technology, pulsed electromagnetic field (PEMF) treatment has been proven to be efficient in promoting osteogenesis. However, the potential bone protective effect and mechanism of PEMF on abnormal subchondral bone remodeling in TMJOA are unknown.MethodsUnilateral anterior crossbite (UAC) was used to create TMJOA model in rats, and 17β-estradiol (E2) were injected daily to mimic patients with high-physiological levels of estrogen. Mouse osteoblast-like MC3T3-E1 cells treated with recombinant murine IL-1β was used to establish inflammatory environment in vitro. The treatment group were subjected to PEMF (2.0mT, 15 Hz, 2 h/d). Micro-CT scanning, histological staining, real-time PCR and western blotting assays were preformed to observe the changes in the subchondral bone.ResultsAbnormal resorption of subchondral bone induced by UAC, characterized by decreased bone mineral density, increased osteoclast activity and expression of osteoclast-related factors (RANKL) and down-regulated expression of osteogenesis-related factors (OPG, ALP, Runx2 and OCN) at the early stage, could be reversed by PEMF exposure, which was similar to the effect of estrogen. In addition, PEMF exposure and E2 supplement may have a synergistic effect to some extent. Moreover, PEMF exposure could promote the ALP activity and osteogenic mineralization ability of MC3T3-E1 cells. PEMF promoted the expression of factors related to Wnt/β-Catenin signal pathway both in vivo and in vitro.ConclusionsAppropriate PEMF exposure have a protective effect on subchondral bone in TMJOA at early stage, in which canonical Wnt/β-Catenin pathway may be involved. PEMF may be a promising biophysical approach for early intervention of TMJOA in clinic.
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Project description:To investigate differentially expressed miRNAs in synovium of human temporomandibular joint osteoarthritis (TMJOA), we performed miRNA high-throughput sequencing in synovium of human TMJOA.
2022-06-10 | GSE205684 | GEO
Project description:Col2a1 gene mutations cause premature degeneration of knee articular cartilage in disproportionate micromelia (Dmm) and spondyloepiphesial dysplasia congenita (sedc) mice. The present study analyses the temporomandibular joint (TMJ) in Col2a1 mutant mice in order to provide an animal model of TMJ osteoarthritis (OA) that may offer better understanding of the progression of this disease in humans.Dmm/+ mice and controls were compared at two, six, nine and 12 months. Craniums were fixed, processed to paraffin sections, stained with Safranin-O/Fast Green, and analysed with light microscopy. OA was quantified using a Mankin scoring procedure. Unfolded protein response (UPR) assay was performed and immunohistochemistry (IHC) was used to assay for known OA biomarkers.Dmm/+ TMJs showed fissuring of condylar cartilage as early as 6 months of age. Chondrocytes were clustered, leaving acellular regions in the matrix. Significant staining of HtrA1, Ddr2 and Mmp-13 was observed in Dmm/+ mice (p<0.01). We detected upregulation of the UPR in knee but not TMJ.Dmm/+ mice are subject to early-onset OA in the TMJ. We observed upregulation of biomarkers and condylar cartilage degradation concomitant with OA. An upregulated UPR may exacerbate the onset of OA. The Dmm/+ mouse TMJ is a viable model for the study of the progression of OA in humans.
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Project description:Temporomandibular joint osteoarthritis (TMJ OA) is a progressive degenerative disease of the temporomandibular joint (TMJ). The unclear etiology and mechanisms of TMJ OA bring great difficulties to early diagnosis and effective treatment, causing enormous burdens to patients' life and social economics. In this narrative review, we summarized the main pathological changes of TMJ OA, including inflammatory responses, degeneration of extracellular matrix (ECM), abnormal cell biological behaviors (apoptosis, autophagy, and differentiation) in TMJ tissue, and aberrant angiogenesis. All pathological features are closely linked to each other, forming a vicious cycle in the process of TMJ OA, which results in prolonged disease duration and makes it difficult to cure. Various molecules and signaling pathways are involved in TMJ OA pathogenesis, including nuclear factor kappa-B (NF-κB), mitogen-activated protein kinases (MAPKs), extracellular regulated protein kinases (ERKs) and transforming growth factor (TGF)-β signaling pathways et al. One molecule or pathway can contribute to several pathological changes, and the crosstalk between different molecules and pathways can further lead to a complicated condition TMJ OA. TMJ OA has miscellaneous etiology, complex clinical status, depressed treatment results, and poor prognosis. Therefore, novel in-vivo and in-vitro models, novel medicine, materials, and approaches for therapeutic procedures might be helpful for further investigation of TMJ OA. Furthermore, the role of genetic factors in TMJ OA needs to be elucidated to establish more reasonable and effective clinical strategies for diagnosing and treating TMJ OA.
| S-EPMC10316511 | biostudies-literature
Project description:Bone degradation of the condylar surface is seen in temporomandibular joint osteoarthritis (TMJ OA); however, the initial changes occur in the subchondral bone. This cross-sectional study was performed to evaluate 23 subchondral bone imaging biomarkers for TMJ OA. The sample consisted of high-resolution cone beam computed tomography scans of 84 subjects, divided into two groups: TMJ OA (45 patients with TMJ OA) and control (39 asymptomatic subjects). Six regions of each mandibular condyle scan were extracted for computation of five bone morphometric and 18 grey-level texture-based variables. The groups were compared using the Mann-Whitney U-test, and the receiver operating characteristics (ROC) curve was determined for each variable that showed a statically significance difference. The results showed statistically significant differences in the subchondral bone microstructure in the lateral and central condylar regions between the control and TMJ OA groups (P< 0.05). The area under the ROC curve (AUC) for these variables was between 0.620 and 0.710. In conclusion, 13 imaging bone biomarkers presented an acceptable diagnostic performance for the diagnosis of TMJ OA, indicating that the texture and geometry of the subchondral bone microarchitecture may be useful for quantitative grading of the disease.
| S-EPMC7765741 | biostudies-literature
Project description:Bone marrow-derived mesenchymal stem cells (BMSCs) are commonly used seed cells, and BMSC-derived primed cartilage templates have been shown to achieve bone regeneration in bone tissue engineering. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in various cellular processes such as osteogenesis and immune regulation. This study investigated the effects of the AhR endogenous ligand 6-formyl (3,2-b) carbazole (FICZ) on the behavior of BMSCs and cartilage templates as well as the possible underlying molecular mechanisms. AhR expressions in rat bone marrow and isolated BMSCs were detected via immunohistochemistry (IHC) and immunofluorescent staining. Alkaline phosphatase staining and alizarin red staining showed that FICZ treatment enhanced the osteogenic potential of BMSCs without influencing their proliferation. FICZ was shown to alleviate the LPS-induced inflammatory cytokines IL-1β, 6 and TNF-α via the quantitative polymerase chain reaction (qPCR). In the chondrogenic process from BMSCs to primed cartilage templates, the expressions of AhR and its target gene cytochrome P450 subfamily B member 1 (CYP1B1) were inhibited. However, IHC staining demonstrated that AhR was still involved in the subcutaneous ossification of cartilage templates. Then, the effects of FICZ on cartilage templates were investigated. The osteogenic markers were upregulated by FICZ administration. The RAW 264.7 treated by condition medium of FICZ-treated cartilage templates exhibited an anti-inflammatory phenotype. Finally, high-throughput sequencing was applied to analyze the differentially expressed genes (DEGs) in the FICZ-treated cartilage templates. The upregulation of cytochrome P450 subfamily A member 1 (CYP1A1) and sphingomyelin phosphodiesterase 3 (Smpd3) were verified by qPCR, which might be the downstream targets of AhR in the cartilage templates promoting osteogenesis and macrophage polarization. These data implied a beneficial role of FICZ in the regenerative potentials of both BMSCs and primed cartilage templates. The FICZ/AhR axis might be a practical target to achieve optimal bone regeneration.
| S-EPMC9007154 | biostudies-literature
Project description:Background Extracellular matrix (ECM) protein malfunction or defect may lead to temporomandibular joint osteoarthritis (TMJ OA). Dentin sialophophoprotein (DSPP) is a mandibular condylar cartilage ECM protein, and its deletion impacted cell proliferation and other extracellular matrix alterations of postnatal condylar cartilage. However, it remains unclear if long-term loss of function of DSPP leads to TMJ OA. The study aimed to test the hypothesis that long-term haploinsufficiency of DSPP causes TMJ OA. Materials and Methods To determine whether Dspp+/- mice exhibit TMJ OA but no severe tooth defects, mandibles of wild-type (WT), Dspp+/-, and Dspp homozygous (Dspp-/-) mice were analyzed by Micro-computed tomography (micro-CT). To characterize the progression and possible mechanisms of osteoarthritic degeneration over time in Dspp+/- mice over time, condyles of Dspp+/- and WT mice were analyzed radiologically, histologically, and immunohistochemically. Results Micro-CT and histomorphometric analyses revealed that Dspp+/- and Dspp-/- mice had significantly lower subchondral bone mass, bone volume fraction, bone mineral density, and trabecular thickness compared to WT mice at 12 months. Interestingly, in contrast to Dspp-/- mice which exhibited tooth loss, Dspp+/- mice had minor tooth defects. RNA sequencing data showed that haplodeficency of DSPP affects the biological process of ossification and osteoclast differentiation. Additionally, histological analysis showed that Dspp+/- mice had condylar cartilage fissures, reduced cartilage thickness, decreased articular cell numbers and severe subchondral bone cavities, and with signs that were exaggerated with age. Radiographic data showed an increase in subchondral osteoporosis up to 18 months and osteophyte formation at 21 months. Moreover, Dspp+/- mice showed increased distribution of osteoclast in the subchondal bone and increased expression of MMP2, IL-6, FN-1, and TLR4 in the mandibular condylar cartilage. Conclusions Dspp+/- mice exhibit TMJ OA in a time-dependent manner, with lesions in the mandibular condyle attributed to hypomineralization of subchondral bone and breakdown of the mandibular condylar cartilage, accompanied by upregulation of inflammatory markers.
2024-03-19 | GSE261528 | GEO