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  • 1
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    The Off-Label Use of Inhaled Nitric Oxide as a Rescue Therapy in Neonates with Refractory Hypoxemic Respiratory Failure: Therapeutic Response and Risk Factors for Mortality
    MDPI AG ; 2019
    In:  Journal of Clinical Medicine Vol. 8, No. 8 ( 2019-07-27), p. 1113-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 8, No. 8 ( 2019-07-27), p. 1113-
    Abstract: Objectives: The indication of inhaled nitric oxide (iNO) used in preterm infants has not been well defined. Neonates with refractory hypoxemia may benefit from the pulmonary vasodilatory effects of iNO. The aim of this study was to investigate the off-label use of iNO as a rescue therapy. Methods: Between January 2010 and December 2017, all neonates who received iNO as a rescue therapy from a tertiary-level medical center were enrolled, and those who were not diagnosed with persistent pulmonary hypertension of newborn (PPHN) were defined as having received off-label use of iNO. The controls were 636 neonates with severe respiratory failure requiring high-frequency oscillatory ventilation but no iNO. Results: A total of 206 neonates who received iNO as a rescue therapy were identified, and 84 (40.8%) had off-label use. The median (interquartile) gestational age was 30.5 (26.3–37.0) weeks. Neonates receiving iNO had significantly more severe respiratory failure and a higher oxygenation index than the controls (p 〈 0.001). Respiratory distress syndrome and secondary pulmonary hypertension after severe bronchopulmonary dysplasia (BPD) were the most common causes of the off-label iNO prescription. Of the 84 neonates with off-label use of iNO, 53 (63.1%) had initial improvement in oxygenation, but 44 (52.4%) eventually died. The overall mortality rate was 41.7% (86/206). After multivariate logistic regression, extremely preterm (odds ratio [OR] 5.51; p 〈 0.001), presence of pulmonary hemorrhage (OR 2.51; p = 0.036) and severe hypotension (OR 2.78; p = 0.008) were the independent risk factors for final mortality. Conclusions: iNO is applicable to be an off-label rescue therapy for premature neonates with refractory hypoxemia due to severe pulmonary hypertension and bronchopulmonary dysplasia.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm8081113
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2662592-1
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  • 2
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    Clustered Regularly Interspaced Short Palindromic Repeat Analysis of Clonal Complex 17 Serotype III Group B Streptococcus Strains Causing Neonatal Invasive Diseases
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 21 ( 2021-10-27), p. 11626-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 21 ( 2021-10-27), p. 11626-
    Abstract: Group B Streptococcus (GBS) is an important pathogen of neonatal infections, and the clonal complex (CC)-17/serotype III GBS strain has emerged as the dominant strain. The clinical manifestations of CC17/III GBS sepsis may vary greatly but have not been well-investigated. A total of 103 CC17/III GBS isolates that caused neonatal invasive diseases were studied using a new approach based on clustered regularly interspaced short palindromic repeats (CRISPR) loci and restriction fragment length polymorphism (RFLP) analyses. All spacers of CRISPR loci were sequenced and analyzed with the clinical presentations. After CRISPR-RFLP analyses, a total of 11 different patterns were observed among the 103 CRISPR-positive GBS isolates. GBS isolates with the same RFLP patterns were found to have highly comparable spacer contents. Comparative sequence analysis of the CRISPR1 spacer content revealed that it is highly diverse and consistent with the dynamics of this system. A total of 29 of 43 (67.4%) spacers displayed homology to reported phage and plasmid DNA sequences. In addition, all CC17/III GBS isolates could be categorized into three subgroups based on the CRISPR-RFLP patterns and eBURST analysis. The CC17/III GBS isolates with a specific CRISPR-RFLP pattern were more significantly associated with occurrences of severe sepsis (57.1% vs. 29.3%, p = 0.012) and meningitis (50.0% vs. 20.8%, p = 0.009) than GBS isolates with RFLP lengths between 1000 and 1300 bp. Whole-genome sequencing was also performed to verify the differences between CC17/III GBS isolates with different CRISPR-RFLP patterns. We concluded that the CRISPR-RFLP analysis is potentially applicable to categorizing CC17/III GBS isolates, and a specific CRISPR-RFLP pattern could be used as a new biomarker to predict meningitis and illness severity after further verification.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms222111626
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
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  • 3
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    Impacts of Multidrug-Resistant Pathogens and Inappropriate Initial Antibiotic Therapy on the Outcomes of Neonates with Ventilator-Associated Pneumonia
    MDPI AG ; 2020
    In:  Antibiotics Vol. 9, No. 11 ( 2020-10-30), p. 760-
    Details
    In: Antibiotics, MDPI AG, Vol. 9, No. 11 ( 2020-10-30), p. 760-
    Abstract: It is unknown whether neonatal ventilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) pathogens and inappropriate initial antibiotic treatment is associated with poor outcomes after adjusting for confounders. Methods: We prospectively observed all neonates with a definite diagnosis of VAP from a tertiary level neonatal intensive care unit (NICU) in Taiwan between October 2017 and March 2020. All clinical features, therapeutic interventions, and outcomes were compared between the MDR–VAP and non-MDR–VAP groups. Multivariate regression analyses were used to investigate independent risk factors for treatment failure. Results: Of 720 neonates who were intubated for more than 2 days, 184 had a total of 245 VAP episodes. The incidence rate of neonatal VAP was 10.1 episodes/per 1000 ventilator days. Ninety-six cases (39.2%) were caused by MDR pathogens. Neonates with MDR–VAP were more likely to receive inadequate initial antibiotic therapy (51.0% versus 4.7%; p 〈 0.001) and had delayed resolution of clinical symptoms (38.5% versus 25.5%; p = 0.034), although final treatment outcomes were comparable with the non-MDR–VAP group. Inappropriate initial antibiotic treatment was not significantly associated with worse outcomes. The VAP-attributable mortality rate and overall mortality rate of this cohort were 3.7% and 12.0%, respectively. Independent risk factors for treatment failure included presence of concurrent bacteremia (OR 4.83; 95% CI 2.03–11.51; p 〈 0.001), septic shock (OR 3.06; 95% CI 1.07–8.72; p = 0.037), neonates on high-frequency oscillatory ventilator (OR 4.10; 95% CI 1.70–9.88; p = 0.002), and underlying neurological sequelae (OR 3.35; 95% CI 1.47–7.67; p = 0.004). Conclusions: MDR–VAP accounted for 39.2% of all neonatal VAP in the neonatal intensive care unit (NICU), but neither inappropriate initial antibiotics nor MDR pathogens were associated with treatment failure. Neonatal VAP with concurrent bacteremia, septic shock, and underlying neurological sequelae were independently associated with final worse outcomes.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics9110760
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2681345-2
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  • 4
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    Multidrug-Resistant Healthcare-Associated Infections in Neonates with Severe Respiratory Failure and the Impacts of Inappropriate Initial Antibiotic Therap
    MDPI AG ; 2021
    In:  Antibiotics Vol. 10, No. 4 ( 2021-04-18), p. 459-
    Details
    In: Antibiotics, MDPI AG, Vol. 10, No. 4 ( 2021-04-18), p. 459-
    Abstract: Background: Multidrug-resistant (MDR) pathogens have emerged as an important issue in neonatal intensive care units (NICUs), especially in critically ill neonates with severe respiratory failure. We aimed to investigate neonatal healthcare-associated infections (HAIs) caused by MDR pathogens and the impacts of inappropriate initial antibiotic therapy on the outcomes. Methods: We retrospectively analyzed all cases of HAIs in neonates with severe respiratory failure in a tertiary-level NICU in Taiwan between January 2014 and May 2020. All clinical features, microbiology, therapeutic interventions, and outcomes were compared between the MDR-HAI and non-MDR HAI groups. Multivariate regression analyses were used to investigate independent risk factors for sepsis-attributable mortality. Results: A total of 275 critically ill neonates with severe respiratory failure who had HAIs were enrolled. Ninety-five cases (34.5%) were caused by MDR pathogens, and 141 (51.3%) cases had positive bacterial cultures from multiple sterile sites. In this cohort, the MDR-HAI group was more likely to receive inappropriate initial antibiotic therapy (51.0% versus 4.7%, respectively; p 〈 0.001) and exhibit delayed control of the infectious focus (52.6% versus 37.8%, respectively; p = 0.021) compared with the non-MDR HAI group. The sepsis-attributable and final in-hospital rates were 21.8% and 37.1%, respectively, and they were comparable between the MDR-HAI and non-MDR HAI groups. Empirically broad-spectrum antibiotics were prescribed in 76.7% of cases, and inappropriate initial antibiotic treatment was not significantly associated with worse outcomes. Independent risk factors for sepsis-attributable mortality in neonates with severe respiratory failure included the presence of septic shock (OR: 3.61; 95% CI: 1.54–8.46; p = 0.003), higher illness severity (OR: 1.33; 95% CI: 1.04–1.72; p = 0.026), and neonates with bronchopulmonary dysplasia (OR: 2.99; 95% CI: 1.47–6.09; p = 0.003). Conclusions: MDR pathogens accounted for 34.5% of all neonatal HAIs in the NICU, but neither MDR pathogens nor inappropriate initial antibiotics were associated with final adverse outcomes. Because the overuse of broad-spectrum antibiotics has emerged as an important issue in critically ill neonates, the implementation of antimicrobial stewardship to promote the appropriate use of antimicrobials is urgently needed.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics10040459
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2681345-2
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  • 5
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    Risk Factors and Outcomes of Recurrent Candidemia in Children: Relapse or Re-Infection?
    MDPI AG ; 2019
    In:  Journal of Clinical Medicine Vol. 8, No. 1 ( 2019-01-16), p. 99-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 8, No. 1 ( 2019-01-16), p. 99-
    Abstract: In this paper, our aim was to investigate the incidence, clinical characteristics, risk factors, and outcomes of recurrent candidemia in children. We retrospectively reviewed all children with candidemia from a medical center in Taiwan between 2004 and 2015. Two episodes of candidemia ≥30 days apart with clinical and microbiological resolution in the interim were defined as “late recurrence”, and those that had 8–29 days apart from previous episodes were defined as “early recurrence”. 45 patients (17.2%) had 57 episodes of recurrent candidemia, and 24 had 28 episodes of late recurrent candidemia. The median time between recurrences was 1.8 months (range: 〈 1 month to 13 months). Of those, 29 had relapsed candidemia and 28 were re-infected by different Candida species (n = 24) or by different strains (n = 4). Recurrent candidemia patients were more likely to require echinocandins treatment, had a longer duration of candidemia, and higher rate of treatment failure (p = 0.001, 0.014, and 0.012, respectively). Underlying gastrointestinal diseases (Odds ratio (OR) 3.84; 95% Confidence interval (CI) 1.81–8.12) and neurological sequelae (OR 2.32; 95% CI 1.15–4.69) were independently associated with the development of recurrent candidemia. 17.2% of pediatric patients with candidemia developed recurrent candidemia, and approximately half were re-infected. Underlying gastrointestinal diseases and neurological sequelae were the independent risk factors for recurrent candidemia.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm8010099
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
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  • 6
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    Genomic Characterization of Serotype III/ST-17 Group B Streptococcus Strains with Antimicrobial Resistance Using Whole Genome Sequencing
    MDPI AG ; 2021
    In:  Biomedicines Vol. 9, No. 10 ( 2021-10-15), p. 1477-
    Details
    In: Biomedicines, MDPI AG, Vol. 9, No. 10 ( 2021-10-15), p. 1477-
    Abstract: Background: Antibiotic-resistant type III/ST-17 Streptococcus agalactiae (group B Streptococcus, GBS) strain is predominant in neonatal invasive GBS diseases. We aimed to investigate the antibiotic resistance profiles and genetic characteristics of type III/ST-17 GBS strains. Methods: A total of 681 non-duplicate GBS isolates were typed (MLST, capsular types) and their antibiotic resistances were performed. Several molecular methods (WGS, PCR, sequencing and sequence analysis) were used to determine the genetic context of antibiotic resistant genes and pili genes. Results: The antibiotic resistant rates were significantly higher in type Ib (90.1%) and type III (71.1%) GBS isolates. WGS revealed that the loss of PI-1 genes and absence of ISSag5 was found in antibiotic-resistant III/ST-17 GBS isolates, which is replaced by a ~75-kb integrative and conjugative element, ICESag37, comprising multiple antibiotic resistance and virulence genes. Among 190 serotype III GBS isolates, the most common pilus island was PI-2b (58.4%) alone, which was found in 81.3% of the III/ST-17 GBS isolates. Loss of PI-1 and ISSag5 was significantly associated with antibiotic resistance (95.5% vs. 27.8%, p 〈 0.001). The presence of ICESag37 was found in 83.6% of all III/ST-17 GBS isolates and 99.1% (105/106) of the antibiotic-resistant III/ST-17 GBS isolates. Conclusions: Loss of PI-1 and ISSag5, which is replaced by ICESag37 carrying multiple antibiotic resistance genes, accounts for the high antibiotic resistance rate in III/ST-17 GBS isolates. The emerging clonal expansion of this hypervirulent strain with antibiotic resistance after acquisition of ICESag37 highlights the urgent need for continuous surveillance of GBS infections.
    Type of Medium: Online Resource
    ISSN: 2227-9059
    URL: Article
    DOI: 10.3390/biomedicines9101477
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 7
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    Clinical and Microbiological Characteristics of Neonates with Candidemia and Impacts of Therapeutic Strategies on the Outcomes
    MDPI AG ; 2022
    In:  Journal of Fungi Vol. 8, No. 5 ( 2022-04-29), p. 465-
    Details
    In: Journal of Fungi, MDPI AG, Vol. 8, No. 5 ( 2022-04-29), p. 465-
    Abstract: Neonatal candidemia is associated with significant morbidities and a high mortality rate. We aimed to investigate the clinical characteristics of Candida bloodstream infections in neonates and the impact of therapeutic strategies on the outcomes. We identified all the neonates with candidemia from a medical center in Taiwan over an 18-year period (2003–2021) and analyzed them. Clinical isolates were confirmed by DNA sequencing, and antifungal susceptibility testing was performed. The prognostic factors associated with clinical treatment failure (30-day, all-cause mortality and persistent candidemia 〉 72 h after antifungal agents) and in-hospital mortality were analyzed using logistic regression modeling. A total of 123 neonates with 139 episodes of candidemia were included in the study. The median (IQR) gestational age and birth weight of the neonates with candidemia were 29.0 (26.0–35.0) weeks and 1104.0 (762.0–2055) g, respectively. The most common Candida spp. was Candida albicans (n = 57, 41.0%), followed by C. parapsilosis (n = 44, 31.7%), Candida guilliermondii (n = 12, 8.6%), and C. glabrata (n = 11, 7.9%). The overall susceptibility to fluconazole was 81.3%, and the resistant rates against other antifungal agents were less than 3%. The cumulative mortality rate at 7 and 30 days after the first episode of candidemia was 11.3% and 32.3%, respectively. The overall in-hospital mortality rate was 42.3%. The treatment outcomes did not change over the study period and were not affected by delayed initiation of antifungal agents. Multivariate analysis showed that delayed catheter removal (odds ratio [OR], 5.54; 95% confidence interval [CI] : 1.93–15.86, p = 0.001), septic shock (OR, 7.88; 95% CI: 2.83–21.93, p 〈 0.001), and multiple chronic comorbidities (OR, 8.71; 95% CI: 1.82–41.81, p = 0.007) were independently associated with the final in-hospital mortality. We concluded that the overall mortality of neonatal candidemia has remained consistently high over the past decade. Prompt early catheter removal and an aggressive treatment strategy for neonatal candidemia with septic shock would be critical to improving patient outcomes.
    Type of Medium: Online Resource
    ISSN: 2309-608X
    URL: Article
    DOI: 10.3390/jof8050465
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2784229-0
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  • 8
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    Risk Factors of Initial Inappropriate Antibiotic Therapy and the Impacts on Outcomes of Neonates with Gram-Negative Bacteremia
    MDPI AG ; 2020
    In:  Antibiotics Vol. 9, No. 4 ( 2020-04-23), p. 203-
    Details
    In: Antibiotics, MDPI AG, Vol. 9, No. 4 ( 2020-04-23), p. 203-
    Abstract: Background: Timely appropriate empirical antibiotic plays an important role in critically ill patients with gram-negative bacteremia. However, the relevant data and significant impacts have not been well studied in the neonatal intensive care unit (NICU). Methods: An 8-year (1 January 2007–31 December 2014) cohort study of all NICU patients with gram-negative bacteremia (GNB) in a tertiary-care medical center was performed. Inadequate empirical antibiotic therapy was defined when a patient did not receive any antimicrobial agent to which the causative microorganisms were susceptible within 24 h of blood culture sampling. Neonates with GNB treated with inadequate antibiotics were compared with those who received initial adequate antibiotics. Results: Among 376 episodes of Gram-negative bacteremia, 75 (19.9%) received inadequate empirical antibiotic therapy. The cause of inadequate treatment was mostly due to the pathogen resistance to prescribed antibiotics (88.0%). Bacteremia caused by Pseudomonas aeruginosa (Odds ratio [OR]: 20.8, P 〈 0.001) and extended spectrum β-lactamase (ESBL)-producing bacteria (OR: 18.4, P 〈 0.001) had the highest risk of inadequate treatment. Previous exposure with third generation cephalosporin was identified as the only independent risk factor (OR: 2.52, 95% CI: 1.18–5.37, P = 0.018). Empirically inadequately treated bacteremias were significantly more likely to have worse outcomes than those with adequate therapy, including a higher risk of major organ damage (20.0% versus 6.6%, P 〈 0.001) and infectious complications (25.3% versus 9.3%, P 〈 0.001), and overall mortality (22.7% versus 11.0%, P = 0.013). Conclusions: Inadequate empirical antibiotic therapy occurs in one-fifth of Gram-negative bacteremias in the NICU, and is associated with worse outcomes. Additional prospective studies are needed to elucidate the optimal timing and aggressive antibiotic regimen for neonates who are at risk of antibiotic-resistant Gram-negative bacteremia.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics9040203
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2681345-2
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  • 9
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    Effect of Freshly Isolated Bone Marrow Mononuclear Cells and Cultured Bone Marrow Stromal Cells in Graft Cell Repopulation and Tendon-Bone Healing after Allograft Anterior Cruciate Ligament Reconstruction
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 6 ( 2021-03-10), p. 2791-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 6 ( 2021-03-10), p. 2791-
    Abstract: Graft cell repopulation and tendon-bone tunnel healing are important after allograft anterior cruciate ligament reconstruction (ACLR). Freshly isolated bone marrow mononuclear cells (BMMNCs) have the advantage of short isolation time during surgery and may enhance tissue regeneration. Thus, we hypothesized that the effect of intra-articular BMMNCs in post-allograft ACLR treatment is comparable to that of cultured bone marrow stromal cells (BMSCs). A rabbit model of hamstring allograft ACLR was used in this study. Animals were randomly assigned to the BMMNC, BMSC, and control groups. Fresh BMMNCs isolated from the iliac crest during surgery and cultured BMSCs at passage four were used in this study. A total of 1 × 107 BMMNCs or BMSCs in 100 µL phosphate-buffered saline were injected into the knee joint immediately after ACLR. The control group was not injected with cells. At two and six weeks post operation, we assessed graft cell repopulation with histological and cell tracking staining (PKH26), and tendon-bone healing with histological micro-computed tomography and immunohistochemical analyses for collagen I and monocyte chemoattractant protein-1 (MCP1). At two weeks post operation, there was no significant difference in the total cell population within the allograft among the three groups. However, the control group showed significantly higher cell population within the allograft than that of BM cell groups at six weeks. Histological examination of proximal tibia revealed that the intra-articular delivered cells infiltrated into the tendon-bone interface. Compared to the control group, the BM cell groups showed broader gaps with interfacial fibrocartilage healing, similar collagen I level, and higher MCP1 expression in the early stage. Micro-CT did not reveal any significant difference among the three groups. BMMNCs and BMSCs had comparable effects on cell repopulation and interfacial allograft-bone healing. Intra-articular BM cells delivery had limited benefits on graft cell repopulation and caused higher inflammation than that in the control group in the early stage, with fibrocartilage formation in the tendon-bone interface after allograft ACLR.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22062791
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
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  • 10
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    Ablation of Discoidin Domain Receptor 1 Provokes an Osteopenic Phenotype by Regulating Osteoblast/Osteocyte Autophagy and Apoptosis
    MDPI AG ; 2022
    In:  Biomedicines Vol. 10, No. 9 ( 2022-09-02), p. 2173-
    Details
    In: Biomedicines, MDPI AG, Vol. 10, No. 9 ( 2022-09-02), p. 2173-
    Abstract: Discoidin domain receptor 1 (DDR1) is a collagen receptor that belongs to the receptor tyrosine kinase family. We have previously shown that DDR1 plays a crucial role during bone development, resulting in dwarfism and a short stature in osteoblast-specific knockout mice (OKO mice). However, the detailed pathophysiological effects of DDR1 on bone development throughout adulthood have remained unclear. This study aims to identify how DDR1 regulates osteoblast and osteocyte functions in vivo and in vitro during bone development in adulthood. The metabolic changes in bone tissues were analyzed using Micro-CT and immunohistochemistry staining (IHC) in vivo; the role of DDR1 in regulating osteoblasts was examined in MC3T3-E1 cells in vitro. The Micro-CT analysis results demonstrated that OKO mice showed a 10% reduction in bone-related parameters from 10 to 14 weeks old and a significant reduction in cortical thickness and diameter compared with flox/flox control mice (FF) mice. These results indicated that DDR1 knockout in OKO mice exhibiting significant bone loss provokes an osteopenic phenotype. The IHC staining revealed a significant decrease in osteogenesis-related genes, including RUNX2, osteocalcin, and osterix. We noted that DDR1 knockout significantly induced osteoblast/osteocyte apoptosis and markedly decreased autophagy activity in vivo. Additionally, the results of the gain- and loss-of-function of the DDR1 assay in MC3T3-E1 cells indicated that DDR1 can regulate the osteoblast differentiation through activating autophagy by regulating the phosphorylation of the mechanistic target of rapamycin (p-mTOR), light chain 3 (LC3), and beclin-1. In conclusion, our study highlights that the ablation of DDR1 results in cancellous bone loss by regulating osteoblast/osteocyte autophagy. These results suggest that DDR1 can act as a potential therapeutic target for managing cancellous bone loss.
    Type of Medium: Online Resource
    ISSN: 2227-9059
    URL: Article
    DOI: 10.3390/biomedicines10092173
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2720867-9
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