Febrile Seizure Causes Deficit in Social Novelty, Gliosis, and Proinflammatory Cytokine Response in the Hippocampal CA2 Region in Rats.

Febrile seizure (FS), which occurs as a response to fever, is the most common seizure that occurs in infants and young children. FS is usually accompanied by diverse neuropsychiatric symptoms, including impaired social behaviors; however, research on neuropsychiatric disorders and hippocampal inflammatory changes following febrile seizure occurrences is very limited. Here, we provide evidence linking FS occurrence with ASD pathogenesis in rats. We developed an FS juvenile rats model and found ASD-like abnormal behaviors including deficits in social novelty, repetitive behaviors, and hyperlocomotion. In addition, FS model juvenile rats showed enhanced levels of gliosis and inflammation in the hippocampal CA2 region and cerebellum. Furthermore, abnormal levels of social and repetitive behaviors persisted in adults FS model rats. These findings suggest that the inflammatory response triggered by febrile seizures in young children could potentially serve as a mediator of social cognitive impairments.

No Difference in Clinical Outcomes and Survivorship for Robotic, Navigational, and Conventional Primary Total Knee Arthroplasty with a Minimum Follow-up of 10 Years.

Background: Computer-assisted surgery, including robotic and navigational total knee arthroplasty (TKA), has been proposed as a technique used to improve alignment of implants. The purpose of this study was to compare the clinical and radiological outcomes during a minimum follow-up period of 10 years among robotic, navigational, and conventional TKA. Methods: A total of 855 knees (robotic group, 194; conventional group, 270; and navigational group, 391) were available for physical and radiological examinations over a mean follow-up period of 10 years. The survival rate was analyzed using the Kaplan-Meier method based on the survival endpoint. The Hospital for Special Surgery score, Western Ontario and McMaster Universities Osteoarthritis Index, Knee Society Score, and range of motion were used for clinical evaluation. The hip-knee-ankle (HKA) axis angle, the coronal inclination of femoral and tibial components, and the presence of radiolucent lines were also assessed at the final follow-up. Results: All clinical assessments at the final follow-up revealed improvements in the three groups without any significant difference among the groups (p > 0.05). The cumulative 10-year survival rate was 97.4% in the robotic group, 96.6% in the conventional group, and 98.2% in the navigational group, with no significant difference (p = 0.447). The rates of complication-associated surgery were not significantly different among the groups (p = 0.907). Only the proportion of outliers in the HKA axis angle showed a significant difference (p = 0.001), but other radiological outcomes were not significantly different among the three groups. Conclusions: Our study demonstrated satisfactory survival rates for robotic, navigational, and conventional TKAs and similar clinical outcomes during the long-term follow-up. Larger studies with continuous serial data are needed to confirm these findings.

Protective effect of GK2 fused BLVRA protein against oxidative stress-induced dopaminergic neuronal cell damage.

It is well known that oxidative stress is highly associated with Parkinson's disease (PD), and biliverdin reductase A (BLVRA) is known to have antioxidant properties against oxidative stress. In this study, we developed a novel N-acetylgalactosamine kinase (GK2) protein transduction domain (PTD) derived from adenosine A2A and fused with BLVRA to determine whether the GK2-BLVRA fusion protein could protect dopaminergic neuronal cells (SH-SY5Y) from oxidative stress in vitro and in vivo using a PD animal model. GK2-BLVRA was transduced into various cells, including SH-SY5Y cells, without cytotoxic effects, and this fusion protein protected SH-SY5Y cells and reduced reactive oxygen species production and DNA damage after 1-methyl-4-phenylpyridinium (MPP+ ) exposure. GK2-BLVRA suppressed mitogen-activated protein kinase (MAPK) activation and modulated apoptosis-related protein (Bcl-2, Bax, cleaved Caspase-3 and -9) expression levels. In the PD animal model, GK2-BLVRA transduced into the substantia nigra crossed the blood-brain barrier and markedly reduced dopaminergic neuronal cell death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animals. These results indicate that our novel PTD GK-2 is useful for the transduction of protein, and GK2-BLVRA exhibits a beneficial effect against dopaminergic neuronal cell death in vitro and in vivo, suggesting that BLVRA can be used as a therapeutic agent for PD.

Diet-related complications according to the timing of enteral nutrition support in patients who recovered from out-of-hospital cardiac arrest: a propensity score matched analysis.

BACKGROUND: A proper nutritional plan for resuscitated patients is important in intensive care; however, specific nutritional guidelines have not yet been established. This study aimed to determine the incidence of diet-related complications that were affected by the timing of enteral nutrition in resuscitated patients after cardiac arrest. METHODS: This retrospective and 1:1 propensity score matching study involved patients who recovered after nontraumatic, out-of-hospital cardiac arrest at a tertiary hospital. Patients were divided into an early nutrition support (ENS) group and a delayed nutrition support (DNS) group according to the nutritional support time within 48 hours after admission. The incidence of major clinical complications was compared between the groups. RESULTS: A total of 46 patients (ENS: 23, DNS: 23) were enrolled in the study. There were no differences in body mass index, comorbidity, and time of cardiopulmonary resuscitation between the two groups. There were 9 patients (ENS: 4, DNS: 5) with aspiration pneumonia; 4 patients (ENS: 2, DNS: 2) with regurgitation; 1 patient (ENS: 0, DNS: 1) with ileus; 21 patients (ENS: 10, DNS: 11) with fever; 13 patients (ENS: 8, DNS: 5) with hypoglycemia; and 20 patients (ENS: 11, DNS: 9) with hyperglycemia. The relative risk of each complication during post-resuscitation care was no different between groups. CONCLUSIONS: There was a similar incidence of diet-related complications during post cardiac arrest care according to the timing of enteral nutrition.

Febrile Seizures Cause Depression and Anxiogenic Behaviors in Rats.

Febrile seizure (FS) is a common type of seizure occurring in human during infancy and childhood. Although an epileptic seizure is associated with psychiatric disorders and comorbid diseases such as depression, anxiety, autism spectrum disorders, sleep disorders, attention deficits, cognitive impairment, and migraine, the causal relationship between FS and psychiatric disorders is poorly understood. The objective of the current study was to investigate the relationship of FS occurrence in childhood with the pathogenesis of anxiety disorder and depression using an FS rat model. We induced febrile seizures in infantile rats (11 days postnatal) using a mercury vapor lamp. At 3 weeks and 12 weeks after FS induction, we examined behaviors and recorded local field potentials (LFPs) to assess anxiety and depression disorder. Interestingly, after FS induction in infantile rats, anxiogenic behaviors and depression-like phenotypes were found in both adult and juvenile FS rats. The analysis of LFPs revealed that 4-7 Hz hippocampal theta rhythm, a neural oscillatory marker for anxiety disorder, was significantly increased in FS rats compared with their wild-type littermates. Taken together, our findings suggest that FS occurrence in infants is causally related to increased levels of anxiety-related behaviors and depression-like symptoms in juvenile and adult rodents.

No difference of survival between cruciate retaining and substitution designs in high flexion total knee arthroplasty.

The aim of this study was to compare the long-term implant survival and outcomes in patients with high-flexion cruciate-retaining (CR) or high-flexion posterior cruciate-substituting (PS) knee implants. A total of 253 knees (CR group: 159 vs. PS group: 94) were available for examination over a mean follow-up of 10 years. Clinical outcomes were assessed including the Hospital for Special Surgery score, Knee Society score and Western Ontario and McMaster Universities Osteoarthritis Index score at the final follow-up. Radiologic measurements were also assessed including the hip-knee-ankle angle and radiolucent lines according to the KSS system at the final follow-up. The survival rate was analyzed using the Kaplan-Meier method. At the final follow-up, the mean total HSS scores were similar between the two groups (p = 0.970). The mean hip-knee-ankle angle at the final follow-up was similar between groups (p = 0.601). The 10- and 15-year survival rates were 95.4% and 93.3% in the CR group and 92.7% and 90.9% in the PS group, respectively, with no significant difference. Similar clinical and radiographic outcomes could be achieved with both the high-flexion CR and high-flexion PS total knee designs without a difference in survival rate after a 10-year follow-up.

Recycling silver nanoparticle debris from laser ablation of silver nanowire in liquid media toward minimum material waste.

As silver nanowires (Ag NWs) are usually manufactured by chemical synthesis, a patterning process is needed to use them as functional devices. Pulsed laser ablation is a promising Ag NW patterning process because it is a simple and inexpensive procedure. However, this process has a disadvantage in that target materials are wasted owing to the subtractive nature of the process involving the removal of unnecessary materials, and large quantities of raw materials are required. In this study, we report a minimum-waste laser patterning process utilizing silver nanoparticle (Ag NP) debris obtained through laser ablation of Ag NWs in liquid media. Since the generated Ag NPs can be used for several applications, wastage of Ag NWs, which is inevitable in conventional laser patterning processes, is dramatically reduced. In addition, electrophoretic deposition of the recycled Ag NPs onto non-ablated Ag NWs allows easy fabrication of junction-enhanced Ag NWs from the deposited Ag NPs. The unique advantage of this method lies in using recycled Ag NPs as building materials, eliminating the additional cost of junction welding Ag NWs. These fabricated Ag NW substrates could be utilized as transparent heaters and stretchable TCEs, thereby validating the effectiveness of the proposed process.

Increased joint obliquity after open-wedge high tibial osteotomy induces pain in the lateral compartment: a comparative analysis of the minimum 4-year follow-up outcomes using propensity score matching.

PURPOSE: To analyze the effects of increased medial proximal tibial angle (MPTA) on the clinical outcomes and cartilage deterioration in the lateral compartment after a mean follow-up period of 4 years following open-wedge high tibial osteotomy (OWHTO) using propensity score matching (PSM) analysis. METHODS: Among 376 knees treated with OWHTO for medial unicompartmental osteoarthritis with varus deformity, 36 knees with MPTA increase of > 95° and 108 knees with MPTA increase of < 95° at the final follow-up were included. The baseline prognostic factors [age, sex, preoperative hip-knee-ankle (HKA) angle, body mass index, and preoperative knee range of motion] were equalized between the 2 groups using PSM; consequently, 31 pairs of patients were compared. The radiographic and clinical outcomes, including lateral compartment pain, were assessed. For 18 patients in each group, second-look arthroscopy and cartilage status assessment were performed. RESULTS: The preoperative demographics were similar between the groups. At the final follow-up, the HKA angle and joint line obliquity were significantly higher in the increased MPTA group. No significant differences were observed in the clinical outcomes between the groups. On second-look arthroscopy, significant cartilage deterioration of the lateral compartment was not observed in either group. Pain in the lateral compartment was experienced significantly more frequently in the increased MPTA group (p < 0.01). CONCLUSION: Although excessively increased MPTA after HTO had no significant effects on the clinical outcomes and cartilage deterioration in the lateral compartment at the minimum 4-year follow-up, lateral compartment pain was experienced significantly more frequently in the increased MPTA group.

Transglutaminase-2 regulates Wnt and FoxO3a signaling to determine the severity of osteoarthritis.

Transglutaminase 2 (TG2), also known as tissue transglutaminase, is a calcium-dependent enzyme that has a variety of intracellular and extracellular substrates. TG2 not only increases in osteoarthritis (OA) tissue but also affects the progression of OA. However, it is still unclear how TG2 affects cartilage degradation in OA at the molecular level. Surgically induced OA lead to an increase of TG2 in the articular cartilage and growth plate, and it was dependent on TGFß1 in primary chondrocytes. The inhibition of TG2 enzymatic activity with intra-articular injection of ZDON, the peptide-based specific TG2 inhibitor, ameliorated the severity of surgically induced OA as well as the expression of MMP-3 and MMP-13. ZDON attenuated MMP-3 and MMP-13 expression in TGFß- and calcium ionophore-treated chondrocytes in a Runx2-independent manner. TG2 inhibition with ZDON suppressed canonical Wnt signaling through a reduction of ß-catenin, which was mediated by ubiquitination-dependent proteasomal degradation. In addition, TG2 activation by a calcium ionophore enhanced the phosphorylation of AMPK and FoxO3a and the nuclear translocation of FoxO3a, which was responsible for the increase in MMP-13. In conclusion, TG2 plays an important role in the pathogenesis of OA as a major catabolic mediator that affects the stability of ß-catenin and FoxO3a-mediated MMP-13 production.

The KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children: Part 2. Management of H1-Antihistamine-Refractory Chronic Urticaria.

Quite a few patients with chronic spontaneous urticaria (CSU) are refractory to H1-antihistamines, even though the dose of H1-antihistamines is increased up to 4-fold. CSU that is not controlled with H1-antihistamines results in increased disease burden. Several immunomodulators have been used to manage these patients. The guidelines reported herein are connected to Part 1 of the KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children, and aimed to provide evidence-based recommendations for the management of H1-antihistamine-refractory CSU. Part 2 focuses on the more commonly used additional treatment options for refractory CSU, including omalizumab, cyclosporine, leukotriene receptor antagonist, dapsone, methotrexate, and phototherapy. The evidence to support their efficacy, dosing, safety, and selection of these agents is systematically reviewed. To date, for patients with refractory CSU, the methodologically sound data to evaluate the use of omalizumab has been growing; however, the evidence of other immunomodulators and phototherapy is still insufficient. Therefore, an individualized stepwise approach with a goal of achieving complete symptom control and minimizing side effects can be recommended. Larger controlled studies are needed to elevate the level of evidence to select a rational therapeutic agent for patients with refractory CSU.

The KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children: Part 1. Definition, Methodology and First-line Management.

Chronic spontaneous urticaria (CSU) is defined as the occurrence of spontaneous wheals, angioedema, or both for >6 weeks in the absence of specific causes. It is a common condition associated with substantial disease burden both for affected individuals and societies in many countries, including Korea. CSU frequently persists for several years and requires high-intensity treatment; therefore, patients experience deteriorations in quality of life and medication-associated complications. During the last decade, there have been major advances in the pharmacological treatment of CSU and there is an outstanding need for evidence-based guidelines that reflect clinical practice in Korea. The guidelines reported here represent a joint initiative of the Korean Academy of Asthma, Allergy and Clinical Immunology and the Korean Dermatological Association, and aim to provide evidence-based guidance for the management of CSU in Korean adults and children. In Part 1, disease definition, guideline scope and development methodology as well as evidence-based recommendations on the use of antihistamines and corticosteroids are summarized.

Correction to: Immediate and delayed hypersensitivity after intra-arterial injection of iodinated contrast media: a prospective study in patients with coronary angiography.

The original version of this article, published on 01 April 2019, unfortunately contained a mistake. The presentation of Fig. 1 was incorrect. The corrected figure is given below.

Searching for the Culprit Drugs for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis from a Nationwide Claim Database in Korea.

BACKGROUND: Ethnic differences exist in relation to culprit drugs for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We wanted to determine culprit drugs for SJS and TEN in Korean population. OBJECTIVE: To evaluate culprit drugs for SJS and TEN by applying an algorithm for assessment of drug causality for epidermal necrolysis (ALDEN) in a nationwide administrative database. METHODS: We used the claims database, which included claims data for the entire South Korean population. A retrospective cohort study was conducted by collecting subjects who were first diagnosed with SJS and TEN in 2011. All drugs prescribed to the subjects were reviewed and scored according to the ALDEN score. Drugs with an ALDEN score ≥2 were considered culprit drugs. RESULTS: A total of 187 subjects were included in the culprit drug analysis; 33 very probable, 101 probable, and 57 possible culprit drugs were identified for SJS and TEN according to the ALDEN score. The most frequently suspected culprit drug was allopurinol (19 cases), followed by carbamazepine (17 cases), lamotrigine (13 cases), amoxicillin (9 cases), and dorzolamide (9 cases). Most cases (78.8%, 52 of 66) associated with the use of allopurinol, carbamazepine, lamotrigine, dorzolamide, and methazolamide occurred between 13 and 44 days after initiating the drug. CONCLUSION: We applied the ALDEN score to the claims database to identify possible culprit drugs for SJS and TEN in South Korea. This approach could shed light on research and policymaking for drug adverse reactions.

Degrading products of chondroitin sulfate can induce hypertrophy-like changes and MMP-13/ADAMTS5 production in chondrocytes.

Chondroitin sulfate (CS) is the most abundant glycosaminoglycan (GAG) in articular cartilage and the loss of CS-GAG occurs early in OA. As a major component of perichondral matrix interacting directly with chondrocytes, the active turnover of CS can affect to break the homeostasis of chondrocytes. Here we employ CS-based 3-dimensional (3D) hydrogel scaffold system to investigate how the degradation products of CS affect the catabolic phenotype of chondrocytes. The breakdown of CS-based ECM by the chondroitinase ABC (ChABC) resulted in a hypertrophy-like morphologic change in chondrocytes, which was accompanied by catabolic phenotypes, including increased MMP-13 and ADAMTS5 expression, nitric oxide (NO) production and oxidative stress. The inhibition of Toll-like receptor 2 (TLR2) or TLR4 with OxPAPC (TLR2 and TLR4 dual inhibitor) and LPS-RS (TLR4-MD2 inhibitor) ameliorated these catabolic phenotypes of chondrocytes by CS-ECM degradation, suggesting a role of CS breakdown products as damage-associated molecular patterns (DAMPs). As downstream signals of TLRs, MAP kinases, NF-kB, NO and STAT3-related signals were responsible for the catabolic phenotypes of chondrocytes associated with ECM degradation. NO in turn reinforced the activation of MAP kinases as well as NFkB signaling pathway. Thus, these results propose that the breakdown product of CS-GAG can recapitulate the catabolic phenotypes of OA.

Periodontitis is associated with an increased risk for proximal colorectal neoplasms.

Interval colorectal cancers detected after colonoscopy are known to be highly associated with proximal colorectal neoplasms (CRNs). This cross-sectional study investigated whether periodontitis could be a risk factor for proximal CRNs in healthy individuals. A total of 2504 subjects who received a colonoscopy and dental exam were enrolled in this study. We divided the subjects into the periodontitis group (n = 216) and the control group (n = 2288). The periodontitis group was defined as subjects who had one or more teeth with a probing pocket depth (PPD) ≥4 mm. The prevalence of proximal CRNs was significantly higher in the periodontitis group (25.0%) than in the control group (12.3%) (P < 0.001). Independent risk factors for proximal CRNs in the multivariate analysis were periodontitis, smoking, age, waist circumference, and triglycerides, and those for proximal advanced CRNs were periodontitis, age, and family history of CRC. However, periodontitis was not a risk factor for overall CRNs and advanced CRNs. Periodontitis was associated with an increased risk of proximal CRNs (odds ratio [OR], 1.525; 95% confidence intervals [95% CI], 1.071-2.172) and proximal advanced CRNs (OR, 2.671; 95% CI, 1.088-6.560). Periodontitis might be associated with proximal CRNs and proximal advanced CRNs.

Immediate and delayed hypersensitivity after intra-arterial injection of iodinated contrast media: a prospective study in patients with coronary angiography.

OBJECTIVES: While hypersensitivity reactions (HSR) to intravenously administered iodinated contrast media (ICM) have been well studied, not much is known about HSR to intra-arterially administered ICM. METHODS: A prospective observational study was performed to evaluate coronary angiography (CAG)-induced ICM hypersensitivity in patients who underwent CAG using ICM including ioversol, a low-osmolar non-ionic monomer, and iodixanol, an iso-osmolar non-ionic dimer. The HSR were investigated through in-patient monitoring after CAG and telephone interview after discharge. RESULTS: A total of 714 patients were enrolled during the observation period, of whom 26 (3.6%) showed immediate HSR and 108 (15.1%) showed delayed HSR. With regard to severity, proportion of immediate HSR grades 1, 2, and 3 was 57.7%, 38.5%, and 3.8%, respectively, whereas that of delayed HSR grades 1, 2, and 3 was 85.2%, 13.9%, and 0.9%, respectively. Multivariate analysis revealed that previous intra-arterial exposure to ICM was an independent risk factor for immediate HSR (odds ratio (OR) 2.92, 95% confidence interval (CI) 1.22-6.96; p = 0.015). Iodixanol was a significant risk factor for delayed HSR (OR 1.61, 95% CI 1.07-2.43; p = 0.024) and correlated with a higher incidence of delayed HSR within 24-h post-ICM administration compared to ioversol. CONCLUSION: The incidence rate of immediate and delayed HSR in intra-arterially administered ICM was 3.6% and 15.1%, respectively. Previous exposure to intra-arterially administered contrast media was a significant risk factor for immediate HSR. Compared to ioversol, iodixanol was associated with relatively earlier and more frequent delayed HSR. KEY POINTS: • In this prospective study, the incidence of immediate and delayed hypersensitivity in intra-arterial injection of contrast media during coronary angiography was 3.6% and 15.1%, respectively. • Delayed hypersensitivity reactions were more common but less severe than immediate hypersensitivity reactions during coronary angiography. • Previous exposure to ICM via intra-arterial route was a significant risk factor for immediate hypersensitivity to intra-arterial contrast medium.

Enhanced Activation of Rac1/Cdc42 and MITF Leads to Augmented Osteoclastogenesis in Autosomal Dominant Osteopetrosis Type II.

The autosomal dominant osteopetrosis type II (ADOII) caused by the mutation of chloride channel 7 (ClC-7) gene is the most common form of adult-onset osteopetrosis. Despite dysfunctional bone resorption, an augmented osteoclast differentiation was reported recently in ADOII patients. DNA sequencing analysis of the ADOII patient's ClC-7 gene identified a known heterozygous mutation, c.643G>A in exon 7, encoding p.Gly215Arg. In vitro osteoclast differentiation from the ADOII patient's peripheral blood mononuclear cells (PBMCs) increased compared with control despite their dysfunctional bone resorbing capacity. Osteoclasts from the ADOII patient's PBMCs and ClC-7 knockdown bone marrow monocytes (BMMs) showed an enhanced Ser-71 phosphorylation of Rac1/Cdc42 and increase of the microphthalmia-associated transcription factor (MITF) and receptor activator of NF-κB (RANK) that can be responsible for the enhanced osteoclast differentiation. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Highly crystalline and uniform conjugated polymer thin films by a water-based biphasic dip-coating technique minimizing the use of halogenated solvents for transistor applications.

The commercialization of organic electronics will require minimizing the use of halogenated solvents used to solution-process organic semiconductors, which is a crucial step for large-area coating methods, such as the dip-coating method. Here, we report a novel biphasic dip-coating method which uses a water-based biphasic solution and produces a uniform, smooth, and crystalline conjugated polymer thin film in the presence of a solvent additive. We demonstrated that a solvent additive with a high boiling point and solubility parameter similar to that of the solution affected the solvent evaporation rate and improved the crystallinity of the dip-coated polymer thin film. The method used to add the solvent strongly influenced how the solvent additive diffused into the polymer solution, which affected the resulting film morphology. The crystallinity and morphology of the polymer films were correlated with the electrical characteristics, and the most crystalline film displayed a high hole field effect mobility of 0.0391 cm2 V-1 s-1 when processed from the solvent mixture without post-treatment. Our findings provide a direction for the development of reliable and promising organic thin film transistor technologies.

KAAACI Evidence-Based Clinical Practice Guidelines for Chronic Cough in Adults and Children in Korea.

Chronic cough is common in the community and causes significant morbidity. Several factors may underlie this problem, but comorbid conditions located at sensory nerve endings that regulate the cough reflex, including rhinitis, rhinosinusitis, asthma, eosinophilic bronchitis, and gastroesophageal reflux disease, are considered important. However, chronic cough is frequently non-specific and accompanied by not easily identifiable causes during the initial evaluation. Therefore, there are unmet needs for developing empirical treatment and practical diagnostic approaches that can be applied in primary clinics. Meanwhile, in referral clinics, a considerable proportion of adult patients with chronic cough are unexplained or refractory to conventional treatment. The present clinical practice guidelines aim to address major clinical questions regarding empirical treatment, practical diagnostic tools for non-specific chronic cough, and available therapeutic options for chronic wet cough in children and unexplained chronic cough in adults in Korea.

Calcium-phosphate complex increased during subchondral bone remodeling affects earlystage osteoarthritis.

An activation of osteoclasts and subchondral bone remodeling is a major histologic feature of early-stage osteoarthritis (OA), which can be accompanied by an increase of calcium (Ca) and phosphate (Pi) level in the subchondral milieu. Considering articular cartilage gets most of nutrition from subchondral bone by diffusion, these micro-environmental changes in subchondral bone can affect the physiology of articular chondrocytes. Here, we have shown that Ca is increased and co-localized with Pi in articular cartilage of early-stage OA. The Ca-Pi complex increased the production of MMP-3 and MMP-13 in the hypertrophic chondrocytes, which was dependent on nuclear factor-kappa B (NF-kB), p38 and extracellular signal-regulated kinase (Erk) 1/2 mitogen-activated protein (MAP) kinase and Signal transducer and activator of transcription 3 (STAT3) signaling. The Ca-Pi complexes increased the expression of endocytosis markers, and the inhibition of the formation of the Ca-Pi complex ameliorated the Ca-Pi complex-mediated increases of MMPs expression in hypertrophic chondrocytes. Our data provide insight regarding the Ca-Pi complex as a potential catabolic mediator in the subchondral milieu and support the pathogenic role of subchondral bone in the early stages of cartilage degeneration.