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OBJECTIVE Studies on the association of oral hygiene indicators with cardiovascular disease in hypertensive patients have been lacking. Oral hygiene is directly or indirectly associated with systemic inflammation, one of the essential mechanisms of cardiovascular disease. Therefore, we hypothesized that oral hygiene would be related to the risk of cardiovascular diseases in hypertensive patients. METHODS We included 52 677 hypertensive participants who completed oral health checkups from the Korean National Health Insurance Service-National Health Screening Cohort between 2003 and 2004. We collected data on periodontitis diagnosis and treatment history, number of teeth loss, number of dental caries, and frequency of tooth brushing from medical records of health claims and oral health examination. The primary outcome was defined as composite outcomes of stroke and myocardial infarction. Follow-up was done until the date of primary outcome, or 31 December 2015. RESULTS During the 11.26 ± 2.39 years (mean ± standard deviation) of the study follow-up, 3292 participants developed primary outcomes [stroke (n = 2430), myocardial infarction (n = 862)]. In multivariable Cox regression analyses, participants with dental caries (≥ 5) were independently associated with occurrence of a primary outcome [adjusted hazard ratio: 1.37; 95% confidence interval (CI):1.10-1.72; P = 0.006]. Frequent tooth brushing (≥ 2 times/day) was significantly related to lower risk of primary outcomes (adjusted hazard ratio: 0.88; 95% CI: 0.81-0.96; P = 0.002). CONCLUSION Our study demonstrated that multiple dental caries were related to the risk of cardiovascular diseases in hypertensive patients. Better oral hygiene may attenuate the risk of cardiovascular events in hypertensive patients.

Background and purposeDiabetes mellitus (DM) is a common metabolic disorder with increased risk of cardiovascular and cerebrovascular complications. However, its relationship with risk of subarachnoid haemorrhage (SAH), the most devastating form of stroke, remains controversial.MethodsTo evaluate the relationship between DM and risk of SAH, we performed a retrospective cohort study using a nationwide, population‐based, health screening database in Korea. We included participants without history of stroke who underwent a nationwide health screening programme between 2003 and 2004. Primary outcome was occurrence of SAH. Participants were followed up until development of SAH or December 2015. Multivariate Cox proportional hazards regression analysis was performed with adjustments for age, sex, systolic blood pressure, total cholesterol, body mass index, physical activity, smoking status, alcohol habit, household income and treatment with antihypertensive agents and statins.ResultsAmong 421 768 study participants, prevalence of DM was 9.6%. During a mean follow-up period of 11.6±1.9 years, 1039 patients developed SAH. Presence of DM was significantly associated with decreased risk of SAH (adjusted HR 0.68; 95% CI 0.53 to 0.86; pConclusionDM and elevated level of fasting blood glucose were inversely associated with risk of SAH. Further studies may elucidate the possibly protective, pathophysiological role played by hyperglycaemia in patients at risk of SAH.

Seomae mugwort, a Korean native variety of Artemisia argyi, exhibits physiological effects against various diseases. However, its effects on osteoarthritis (OA) are unclear. In this study, a Seomae mugwort extract prevented cartilage destruction in an OA mouse model. In vitro and ex vivo analyses revealed that the extract suppressed MMP3, MMP13, ADAMTS4 and ADAMTS5 expression induced by IL‐1β, IL‐6 and TNF‐α and inhibited the loss of extracellular sulphated proteoglycans. In vivo analysis revealed that oral administration of the extract suppressed DMM‐induced cartilage destruction. We identified jaceosidin in Seomae mugwort and showed that this compound decreased MMP3, MMP13, ADAMTS4 and ADAMTS5 expression levels, similar to the action of the Seomae mugwort extract in cultured chondrocytes. Interestingly, jaceosidin and eupatilin combined had similar effects to Seomae mugwort in the DMM‐induced OA model. Induction of IκB degradation by IL‐1β was blocked by the extract and jaceosidin, whereas JNK phosphorylation was only suppressed by the extract. These results suggest that the Seomae mugwort extract and jaceosidin can attenuate cartilage destruction by suppressing MMPs, ADAMTS4/5 and the nuclear factor‐κB signalling pathway by blocking IκB degradation. Thus, the findings support the potential application of Seomae mugwort, and particularly jaceosidin, as natural therapeutics for OA.

Problem Infection is associated with occurrence and worsening of heart failure (HF). However, studies on the association of susceptibility and severe complications of coronavirus disease 2019 (COVID-19) with HF history are limited. Method of study From the Korean nationwide COVID-19 dataset, 212,678 participants with at least one severe acute respiratory syndrome coronavirus 2 real-time reverse transcription polymerase chain reaction (RT PCR) test were included between Jan 1 and June 4, 2020. To investigate the association of HF with susceptibility and severe complications of COVID-19, 1:5 ratio propensity score matching (PSM) and logistic regression analysis were performed. The primary outcome was a composite outcome of mechanical ventilation, intensive care unit admission, and death. Results After PSM, COVID-19 PCR positivity did not show a significant difference according to HF history in multivariable analysis (odds ratio (OR): 0.91, 95% confidence interval (CI) (0.79 - 1.04), p = 0.146). Of 7,630 individuals with confirmed COVID-19 infection, 310 (4.1%) had HF history. The overall primary outcome occurred in 426 (5.6%) individuals, including 159 (2.1%) cases of mechanical ventilation, 254 (3.3%) cases of intensive care unit admission, and 215 (2.8%) cases of death. In multivariate logistic analysis, presence of HF history was associated independently with primary outcome (OR: 1.99, 95% CI: 1.42 - 2.79, p Conclusions Our study demonstrated that HF history is associated poor prognosis, particularly mortality, in COVID-19. Patients with HF can have severe complication if infected with COVID-19; therefore, careful management are necessary. This article is protected by copyright. All rights reserved.

Oral diseases, such as periodontitis and dental caries, can cause systemic inflammation as well as local effects, which is an important contributing factor for obesity. We aimed to investigate the change in body mass index (BMI) according to the presence of periodontitis and oral hygiene indicators. This study enrolled 110,068 participants from the national health screening cohort in Korea from 2009–2010 who underwent an oral health checkup. As oral hygiene indicators, the presence of periodontitis, dental caries, tooth loss, and tooth brushing were assessed. We constructed a linear mixed model for BMI. BMI was repeatedly measured in the health examination until 2015. In the multivariate linear mixed model for BMI, the presence of periodontitis (β = 0.0687, standard error (SE) = 0.0225, p = 0.002), dental caries (β = 0.0735, SE = 0.0152, p &lt, 0.001), and tooth loss (β = 0.1328, SE = 0.0175, p &lt, 0.001) were positively associated with BMI. In contrast, frequent tooth brushing (≥3 times/day) was negatively associated with BMI (β = −0.2610, SE = 0.0306, p &lt, 0.001). The presence of periodontitis, dental caries, and tooth loss may be associated with higher BMI, whereas frequent tooth brushing may be related to lower BMI. Better oral hygiene might be associated with lower BMI. Further study is needed to determine the effect of oral health behavior and dental disease on obesity.

Although Hif‐2α is a master regulator of catabolic factor expression in osteoarthritis development, Hif‐2α inhibitors remain undeveloped. The aim of this study was to determine whether Cirsium japonicum var. maackii (CJM) extract and one of its constituents, apigenin, could attenuate the Hif‐2α‐induced cartilage destruction implicated in osteoarthritis progression. In vitro and in vivo studies demonstrated that CJM reduced the IL‐1β‐, IL‐6, IL‐17‐ and TNF‐α‐induced up‐regulation of MMP3, MMP13, ADAMTS4, ADAMTS5 and COX‐2 and blocked osteoarthritis development in a destabilization of the medial meniscus mouse model. Activation of Hif‐2α, which directly up‐regulates MMP3, MMP13, ADAMTS4, IL‐6 and COX‐2 expression, is inhibited by CJM extract. Although cirsimarin, cirsimaritin and apigenin are components of CJM and can reduce inflammation, only apigenin effectively reduced Hif‐2α expression and inhibited Hif‐2α‐induced MMP3, MMP13, ADAMTS4, IL‐6 and COX‐2 expression in articular chondrocytes. IL‐1β induction of JNK phosphorylation and IκB degradation, representing a critical pathway for Hif‐2α expression, was completely blocked by apigenin in a concentration‐dependent manner. Collectively, these effects indicate that CJM and one of its most potent constituents, apigenin, can lead to the development of therapeutic agents for blocking osteoarthritis development as novel Hif‐2α inhibitors.

Background Cardiovascular risk increases following herpes zoster. We investigated whether treatment with antiviral agents, steroids, and common cardiovascular medications was associated with the risk of postherpetic cardiovascular events. Methods This was a nationwide population-based, retrospective, cohort study using the National Health Insurance Service health claims data in Korea. We included patients with a first-ever diagnosis of herpes zoster in 2003–2014 and no prior cardiovascular event. The primary outcome was the occurrence of composites of myocardial infarction (International Statistical Classification of Diseases, Tenth Revision, code I21) and stroke (codes I60–I63) since the herpes zoster. We analyzed the exposure (intravenous or oral administration) to antiviral agents, steroids, antithrombotics, and statins within ±7 days from the index date of herpes zoster diagnosis. Follow-up was performed until occurrence of the primary outcome, death, or 31 December 2015, whichever came first. Results Of 84 993 patients with herpes zoster, the proportions of patients who received the treatment with antiviral agents, steroids, antithrombotics, and statins were 90.5%, 48.0%, 9.1%, and 7.9%, respectively. During the mean (standard deviation) follow-up period of 5.4 (3.1) years, 1523 patients experienced the primary outcome. Multivariate Cox regression analysis demonstrated that treatment with antiviral agents (adjusted hazard ratio, 0.82; 95% confidence interval, .71–.95) and statins (0.71; .59–.85) were significantly associated with the lower risk of primary outcome. Use of antithrombotics and steroids were not associated with the risk. Conclusions After herpes zoster, treatment with antiviral agents was significantly associated with lower risk of cardiovascular events. We need more information on the cardiovascular protective role of herpes zoster treatments.

3′-Sialyllactose (3′-SL), a natural prebiotic, maintains immune homeostasis and exerts anti-inflammatory and anti-arthritic effects. Although regulatory T cells (Tregs) prevent excessive inflammation and maintain immune tolerance, the effect of 3′-SL on Treg regulation is unclear. This study aimed to investigate the effect of 3′-SL on Treg responses in atopic dermatitis (AD) pathogenesis. Oral administration of 3′-SL reduced AD-like symptoms such as ear, epidermal, and dermal thickness in repeated topical application of house dust mites (HDM) and 2,4-dinitrochlorobenzene (DNCB). 3′-SL inhibited IgE, IL-1β, IL-6, and TNF-α secretion and markedly downregulated AD-related cytokines including IL-4, IL-5, IL-6, IL-13, IL-17, IFN-γ, TNF-α, and Tslp through regulation of NF-κB in ear tissue. Additionally, in vitro assessment of Treg differentiation revealed that 3′-SL directly induced TGF-β-mediated Treg differentiation. Furthermore, 3′-SL administration also ameliorated sensitization and elicitation of AD pathogenesis by suppressing mast cell infiltration and production of IgE and pro-inflammatory cytokines in mouse serum by mediating the Treg response. Furthermore, Bifidobacterium population was also increased by 3′-SL administration as prebiotics. Our data collectively show that 3′-SL has therapeutic effects against AD progression by inducing Treg differentiation, downregulating AD-related cytokines, and increasing the Bifidobacterium population.

Background and purpose 3'-Sialyllactose (3'-SL) is a safe compound that is present in high levels in human milk. Although it has anti-inflammatory properties and supports immune homeostasis, its effect on collagen-induced arthritis (CIA) is unknown. In this study, we investigated the prophylactic and therapeutic effect of 3'-SL on the progression of rheumatoid arthritis (RA) in in vitro and in vivo models. Experimental approach The anti-arthritic effect of 3'-SL was analysed with fibroblast-like synoviocytes in vitro and an in vivo mouse model of CIA. RT-PCR, Western blotting and ELISA were performed to evaluate its effects in vitro. Histological analysis of ankle and knee joints of mice with CIA was performed using immunohistochemistry, as well as safranin-O and haematoxylin staining. Key results 3'-SL markedly alleviated the severity of CIA in the mice by reducing paw swelling, clinical scores, incidence rate, serum levels of inflammatory cytokines and autoantibody production. Moreover, 3'-SL reduced synovitis and pannus formation and suppressed cartilage destruction by blocking secretion of chemokines, pro-inflammatory cytokines, matrix metalloproteinases and osteoclastogenesis via NF-κB signalling. Notably, phosphorylation of p65, which is a key protein in the NF-κB signalling pathway, was totally blocked by 3'-SL in the RA models. Conclusions and implications 3'-SL ameliorated pathogenesis of CIA by suppressing catabolic factor expression, proliferation of inflammatory immune cells and osteoclastogenesis. These effects were mediated via blockade of the NF-κB signalling pathway. Therefore, 3'-SL exerted prophylactic and therapeutic effects and could be a novel therapeutic agent for the treatment of RA.

Patients with myocardial infarction (MI) are at high risk of developing pneumonia. Proton pump inhibitors (PPI) and H2-receptor antagonists (H2RA) are commonly used acid-suppressive medications to the patients with MI for gastrointestinal (GI) protection, which may increase the risk for pneumonia. We evaluated whether PPI, H2RA, and mucoprotective agents without anti-acid properties increase the risk of post-MI pneumonia. We performed a retrospective cohort study based on the National Health Insurance Service—National Sample Cohort in Korea. The study included 3701 patients discharged with MI without prior history of pneumonia. During follow-up, treatments with PPI, H2RA, and mucoprotective agents were collected as time-dependent variables based on the prescription records. We performed multivariate time-dependent Cox regression analyses for the development of post-MI pneumonia. During the mean 4.85 ± 3.75 years follow-up, 999 participants developed pneumonia. In the multivariate analyses (adjusted hazard ratio; 95% confidence interval), the risk for pneumonia was significantly increased in treatment with PPI (2.25; 1.57–3.21) and H2RA (1.50; 1.16–1.93). Meanwhile, the risk for pneumonia was not increased in treatment with mucoprotective agents. When we evaluated GI bleeding event according to the medications as a secondary outcome analysis, mucoprotective agents were associated with increased GI bleeding risk, but PPI and H2RA were not. In the use of the GI medications in the treatment of patients with MI, the influence of these drugs on bleeding and pneumonia should be considered.

Aim Periodontitis is a common chronic inflammatory disease prevalent in diabetes. The aim of this study was to evaluate periodontitis and poor oral hygiene as independent risk factors for either cerebral or myocardial infarction in the diabetes population. Methods This retrospective cohort study included 17,009 patients with diabetes who had participated in a nationwide health-screening programme, including oral health examination, during 2002–2003 in South Korea. Presence of periodontitis, tooth loss and carious teeth were assessed by professional dentists, and the number of tooth brushings per day was evaluated through self-reported questionnaires. The primary study outcome was the development of cerebral or myocardial infarction, based on International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes, up to 31 December 2015. Results The study enrolled 17,009 patients with diabetes. Over the mean 11.64 years of follow-up, 1341 patients presented with either cerebral or myocardial infarction. On multivariable Cox proportional hazards regression analysis, presence of periodontitis was an independent risk factor for either cerebral or myocardial infarction [adjusted hazard ratio (HR): 1.17, 95% confidence interval (CI): 1.02–1.34; P = 0.030]. An increased number of carious teeth (≥5) was also associated with risk of cerebral or myocardial infarction (adjusted HR: 1.67, 95% CI: 1.20–2.32; P = 0.002), whereas frequent tooth brushing (≥2 times/day) was negatively associated with risk of cerebral or myocardial infarction (adjusted HR: 0.79, 95% CI: 0.70–0.90; P Conclusion Early identification and intervention of periodontal disease may be effective in reducing cardiovascular complications in the diabetes population, and improved oral hygiene would probably be associated with lower cardiovascular risk in diabetes.

3′‐Sialyllactose has specific physiological functions in a variety of tissues; however, its effects on osteoarthritic development remain unknown. Here, we demonstrated the function of 3′‐sialyllactose on osteoarthritic cartilage destruction. In vitro and ex vivo, biochemical and histological analysis demonstrated that 3′‐sialyllactose was sufficient to restore the synthesis of Col2a1 and accumulation of sulphated proteoglycan, a critical factor for cartilage regeneration in osteoarthritic development, and blocked the expression of Mmp3, Mmp13 and Cox2 induced by IL‐1β, IL‐6, IL‐17 and TNF‐α, which mediates cartilage degradation. Further, reporter gene assays revealed that the activity of Sox9 as a transcription factor for Col2a1 expression was accelerated by 3′‐sialyllactose, whereas the direct binding of NF‐κB to the Mmp3, Mmp13 and Cox2 promoters was reduced by 3′‐sialyllactose in IL‐1β‐treated chondrocytes. Additionally, IL‐1β induction of Erk phosphorylation and IκB degradation, representing a critical signal pathway for osteoarthritic development, was totally blocked by 3′‐sialyllactose in a dose‐dependent manner. In vivo, 3′‐sialyllactose protected against osteoarthritic cartilage destruction in an osteoarthritis mouse model induced by destabilization of the medial meniscus, as demonstrated by histopathological analysis. Our results strongly suggest that 3′‐sialyllactose may ameliorate osteoarthritic cartilage destruction by cartilage regeneration via promoting Col2a1 production and may inhibit cartilage degradation and inflammation by suppressing Mmp3, Mmp13 and Cox2 expression. The effects of 3′‐sialyllactose could be attributed in part to its regulation of Sox9 or NF‐κB and inhibition of Erk phosphorylation and IκB degradation. Taken together, these effects indicate that 3′‐sialyllactose merits consideration as a natural therapeutic agent for protecting against osteoarthritis.

Although the biological mechanisms underlying the beneficial effects of vitamin B6 on cardiovascular disease (CVD) have been reported on, epidemiological studies have yielded controversial results, and data on the Korean population are limited. This study examined the association between dietary vitamin B6 intake and CVD incidence in Koreans. A total of 9142 participants of the Korean Genome and Epidemiology Study, aged 40&ndash, 69 years, who did not have CVD or cancer at the baseline were included in the analysis. Dietary data were assessed using a validated semi-quantitative food frequency questionnaire. CVD incidence was assessed using biennial questionnaires and confirmed through repeated personal interviews. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression models. After multivariate adjustment, a higher vitamin B6 intake was significantly associated with a decreased CVD risk in men (HR: 0.44, 95% CI: 0.25&ndash, 0.78), no such association was observed in women. Dose-response analysis confirmed the presence of inverse linearity between vitamin B6 intake and CVD incidence in men (p for nonlinearity = 0.3). A higher dietary intake level of vitamin B6 was associated with a reduced CVD risk in Korean men. These observations require further verification in other populations.

Background Although previous studies have shown that short-term exposure to mercury is associated with obesity, it should be noted that mercury is not easily released and that it constantly accumulates in the body. However, few studies have explored the association between chronic mercury exposure and obesity. This study aimed to examine the association between chronic mercury exposure and obesity in Korean adults. Methods The study used baseline data from the Trace Element Study of Korean Adults in Yeungnam area. A total of 495 participants aged 40–69 years who provided the required information (demographic, diet, lifestyle, toenail mercury levels, and health examination results) were included. Toenail mercury levels were measured using neutron-activation analysis. Body mass index and waist circumference were obtained from medical examination. Multivariable-adjusted logistic regression and restricted cubic spline regression were used in the analysis. Results In the fully adjusted logistic regression models, participants with the highest toenail mercury levels had a higher prevalence of obesity (odds ratio [OR]: 3.26, 95 % confidence interval [CI]: 1.79–5.93) and abdominal obesity (OR: 2.30, 95 % CI: 1.15–4.59). In the cubic spline regression model, linear relationships were confirmed between increased toenail mercury levels and higher prevalence of obesity and abdominal obesity (all p > 0.05 for nonlinearity). Conclusions In summary, chronic mercury exposure was associated with higher prevalence of obesity and abdominal obesity in Korean adults. Therefore, the development of public health interventions against environmental exposure of foods is required to manage and prevent obesity.

The effect of calcium consumption in the prevention of type 2 diabetes mellitus (T2DM) remains controversial, and depends on food calcium sources. This prospective study aimed to evaluate the association between calcium-rich food consumption and T2DM incidence among Korean adults. We analyzed the data of 8574 adults aged 40&ndash, 69 years, without a history of T2DM, cardiovascular disease, and cancer at the baseline from the Korean Genome and Epidemiology Study. The consumption of calcium-rich foods was assessed using a validated semi-quantitative food frequency questionnaire. T2DM-related data were collected using biennial questionnaires, health examinations, and clinical tests. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. In the multivariate-adjusted model, yogurt intake was inversely associated with T2DM risk (HR: 0.73, 95% CI: 0.61&ndash, 0.88 in the fourth quartile as compared to the first quartile). However, the intakes of other calcium-rich foods, including milk and anchovies, were not significantly associated with T2DM risk. Yogurt may provide protective effects against T2DM in Korean adults, owing to the beneficial effects of probiotics. Further prospective large-scale cohort studies should be conducted to validate these findings.

Developing and mature chondrocytes constantly interact with and remodel the surrounding extracellular matrix (ECM). Recent research indicates that integrin-ECM interaction is differentially regulated during cartilage formation (chondrogenesis). Integrin signaling is also a key source of the catabolic reactions responsible for joint destruction in both rheumatoid arthritis and osteoarthritis. However, we do not understand how chondrocytes dynamically regulate integrin signaling in such an ECM-rich environment. Here, we found that developing chondrocytes express integrin-β-like 1 (Itgbl1) at specific stages, inhibiting integrin signaling and promoting chondrogenesis. Unlike cytosolic integrin inhibitors, ITGBL1 is secreted and physically interacts with integrins to down-regulate activity. We observed that Itgbl1 expression was strongly reduced in the damaged articular cartilage of patients with osteoarthritis (OA). Ectopic expression of Itgbl1 protected joint cartilage against OA development in the destabilization of the medial meniscus-induced OA mouse model. Our results reveal ITGBL1 signaling as an underlying mechanism of protection against destructive cartilage disorders and suggest the potential therapeutic utility of targeting ITGBL1 to modulate integrin signaling in human disease.

Objective Hypoxia-inducible factor 2α (HIF-2α), encoded by Epas1 , causes osteoarthritic cartilage destruction by regulating the expression of matrix-degrading enzymes. We undertook this study to explore the role of nicotinamide phosphoribosyltransferase (NAMPT or visfatin) in HIF-2α-mediated osteoarthritic cartilage destruction. Methods The expression of HIF-2α, NAMPT and matrix-degrading enzymes was determined at the mRNA and protein levels in human osteoarthritis (OA) cartilage, mouse experimental OA cartilage and primary cultured mouse chondrocytes. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) surgery or intra-articular injection of Ad- Epas1 or Ad- Nampt in wild-type, Epas1 +/− , Epas1 fl/fl ; Col2a1-Cre and Col2a1-Nampt transgenic (TG) mice. Primary cultured mouse chondrocytes were treated with recombinant NAMPT protein or were infected with adenoviruses. Results We found that the Nampt gene is a direct target of HIF-2α in articular chondrocytes and OA cartilage. NAMPT protein, in turn, increased mRNA levels and activities of MMP3, MMP12 and MMP13 in chondrocytes, an action that was necessary for HIF-2α-induced expression of catabolic enzymes. Gain-of-function studies (intra-articular injection of Ad- Nampt; Col2a1-Nampt TG mice) and loss-of-function studies (intra-articular injection of the NAMPT inhibitor FK866) demonstrated that NAMPT is an essential catabolic regulator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery. Conclusions Our findings indicate that NAMPT, whose corresponding gene is a direct target of HIF-2α, plays an essential catabolic role in OA pathogenesis and acts as a crucial mediator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery.

We have shown that cytokine-like 1 (Cytl1) is a novel autocrine regulatory factor that regulates chondrogenesis of mouse mesenchymal cells (Kim, J. S., Ryoo, Z. Y., and Chun, J. S. (2007) J. Biol. Chem. 282, 29359-29367). In this previous work, we found that Cytl1 expression was very low in mesenchymal cells, increased dramatically during chondrogenesis, and decreased during hypertrophic maturation, both in vivo and in vitro. Moreover, exogenous addition or ectopic expression of Cytl1 caused chondrogenic differentiation of mouse limb bud mesenchymal cells. In the current study, we generated a Cytl1 knock-out (Cytl1(-/-)) mouse to investigate the in vivo role of Cytl1. Deletion of the Cytl1 gene did not affect chondrogenesis or cartilage development. Cytl1(-/-) mice also showed normal endochondral ossification and long bone development. Additionally, ultrastructural features of articular cartilage, such as matrix organization and chondrocyte morphology, were similar in wild-type and Cytl1(-/-) mice. However, Cytl1(-/-) mice were more sensitive to osteoarthritic (OA) cartilage destruction. Compared with wild-type littermates, Cytl1(-/-) mice showed more severe OA cartilage destruction upon destabilization of the medial meniscus of mouse knee joints. In addition, expression levels of Cytl1 were markedly decreased in OA cartilage of humans and experimental mice. Taken together, our results suggest that, rather than regulating cartilage and bone development, Cytl1 is required for the maintenance of cartilage homeostasis, and loss of Cytl1 function is associated with experimental OA cartilage destruction in mice.

Summary Osteoarthritis (OA), primarily characterized by cartilage degeneration, is caused by an imbalance between anabolic and catabolic factors. Here, we investigated the role of zinc (Zn 2+ ) homeostasis, Zn 2+ transporters, and Zn 2+ -dependent transcription factors in OA pathogenesis. Among Zn 2+ transporters, the Zn 2+ importer ZIP8 was specifically upregulated in OA cartilage of humans and mice, resulting in increased levels of intracellular Zn 2+ in chondrocytes. ZIP8-mediated Zn 2+ influx upregulated the expression of matrix-degrading enzymes (MMP3, MMP9, MMP12, MMP13, and ADAMTS5) in chondrocytes. Ectopic expression of ZIP8 in mouse cartilage tissue caused OA cartilage destruction, whereas Zip8 knockout suppressed surgically induced OA pathogenesis, with concomitant modulation of Zn 2+ influx and matrix-degrading enzymes. Furthermore, MTF1 was identified as an essential transcription factor in mediating Zn 2+ /ZIP8-induced catabolic factor expression, and genetic modulation of Mtf1 in mice altered OA pathogenesis. We propose that the zinc-ZIP8-MTF1 axis is an essential catabolic regulator of OA pathogenesis.

Developing cartilage serves as a template for long-bone development during endochondral ossification. Although the coupling of cartilage and bone development with angiogenesis is an important regulatory step for endochondral ossification, the molecular mechanisms are poorly understood. One possible mechanism involves the action of Dickkopf (DKK), which is a family of soluble canonical Wnt antagonists with four members (DKK1–4). We initially observed opposite expression patterns of Dkk1 and Dkk2 during angiogenesis and chondrocyte differentiation: downregulation of Dkk1 and upregulation of Dkk2. We examined the in vivo role of Dkk1 and Dkk2 in linking cartilage/bone development and angiogenesis by generating transgenic (TG) mice that specifically express Dkk1 or Dkk2 in chondrocytes, hypertrophic chondrocytes, or endothelial cells. Despite specific expression pattern during cartilage development, chondrocyte- and hypertrophic chondrocyte-specific Dkk1 and Dkk2 TG mice showed normal developmental phenotypes. However, Dkk1 misexpression in endothelial cells resulted in defects of endochondral ossification and reduced skeletal size. The defects are caused by the inhibition of angiogenesis in developing bone and subsequent inhibition of apoptosis of hypertrophic chondrocytes and cartilage resorption. © 2012 American Society for Bone and Mineral Research.