Molecular mechanisms and physiological functions of mitophagy.

Degradation of mitochondria via a selective form of autophagy, named mitophagy, is a fundamental mechanism conserved from yeast to humans that regulates mitochondrial quality and quantity control. Mitophagy is promoted via specific mitochondrial outer membrane receptors, or ubiquitin molecules conjugated to proteins on the mitochondrial surface leading to the formation of autophagosomes surrounding mitochondria. Mitophagy-mediated elimination of mitochondria plays an important role in many processes including early embryonic development, cell differentiation, inflammation, and apoptosis. Recent advances in analyzing mitophagy in vivo also reveal high rates of steady-state mitochondrial turnover in diverse cell types, highlighting the intracellular housekeeping role of mitophagy. Defects in mitophagy are associated with various pathological conditions such as neurodegeneration, heart failure, cancer, and aging, further underscoring the biological relevance. Here, we review our current molecular understanding of mitophagy, and its physiological implications, and discuss how multiple mitophagy pathways coordinately modulate mitochondrial fitness and populations.

A ubiquitin-proteasome pathway degrades the inner nuclear membrane protein Bqt4 to maintain nuclear membrane homeostasis.

Aberrant accumulation of inner nuclear membrane (INM) proteins is associated with deformed nuclear morphology and mammalian diseases. However, the mechanisms underlying the maintenance of INM homeostasis remain poorly understood. In this study, we explored the degradation mechanisms of the INM protein Bqt4 in the fission yeast Schizosaccharomyces pombe. We have previously shown that Bqt4 interacts with the transmembrane protein Bqt3 at the INM and is degraded in the absence of Bqt3. Here, we reveal that excess Bqt4, unassociated with Bqt3, is targeted for degradation by the ubiquitin-proteasome system localized in the nucleus and Bqt3 antagonizes this process. The degradation process involves the Doa10 E3 ligase complex at the INM. Bqt4 is a tail-anchored protein and the Cdc48 complex is required for its degradation. The C-terminal transmembrane domain of Bqt4 was necessary and sufficient for proteasome-dependent protein degradation. Accumulation of Bqt4 at the INM impaired cell viability with nuclear envelope deformation, suggesting that quantity control of Bqt4 plays an important role in nuclear membrane homeostasis.

Single-nucleus RNA sequencing reveals loss of DCT1 renal tubules in HIV Vpr transgenic mice.

Hyponatremia and salt wasting is a common occurance in patients with HIV/AIDS, however, the understanding of its contributing factors is limited. HIV viral protein R (Vpr) contributes to HIV-associated nephropathy. To investigate the effects of Vpr on the distal tubules and on the expression level of the Slc12a3 gene, encoding the Na-Cl cotransporter, which is responsible for sodium reabsorption in distal nephron segments, single-nucleus RNA sequencing was performed on kidney cortices from three wild-type (WT) and three Vpr-transgenic (Vpr Tg) mice. The results showed that the percentage of distal convoluted tubule (DCT) cells was significantly lower in Vpr Tg mice compared with WT mice (P < 0.05), and that in Vpr Tg mice, Slc12a3 expression was not significantly different in DCT cells. The Pvalb+ DCT1 subcluster had fewer cells in Vpr Tg mice compared with WT mice (P < 0.01). Immunohistochemistry demonstrated fewer Slc12a3+Pvalb+ DCT1 segments in Vpr Tg mice. Differential gene expression analysis between Vpr Tg and WT in the DCT cluster showed downregulation of Ier3 gene, which is an inhibitor of apoptosis. The in vitro knockdown of Ier3 by siRNA transfection induced apoptosis in mouse DCT cells. These observations suggest that the salt-wasting effect of Vpr in Vpr Tg mice is likely mediated by Ier3 downregulation in DCT1 cells and loss of Slc12a3+Pvalb+ DCT1 segments.

Application of non-negative matrix factorization in oncology: one approach for establishing precision medicine.

The increase in the expectations of artificial intelligence (AI) technology has led to machine learning technology being actively used in the medical field. Non-negative matrix factorization (NMF) is a machine learning technique used for image analysis, speech recognition, and language processing; recently, it is being applied to medical research. Precision medicine, wherein important information is extracted from large-scale medical data to provide optimal medical care for every individual, is considered important in medical policies globally, and the application of machine learning techniques to this end is being handled in several ways. NMF is also introduced differently because of the characteristics of its algorithms. In this review, the importance of NMF in the field of medicine, with a focus on the field of oncology, is described by explaining the mathematical science of NMF and the characteristics of the algorithm, providing examples of how NMF can be used to establish precision medicine, and presenting the challenges of NMF. Finally, the direction regarding the effective use of NMF in the field of oncology is also discussed.

Pre-milling technique improves the accuracy of posterior femoral condyle cut and reduces the tibial recut in Oxford unicompartmental knee arthroplasty.

BACKGROUND: Recuts are sometimes needed in UKA because of inadequate posterior tibial cut thickness. We investigated the efficacy of a pre-milling technique (the first milling is done prior to the posterior condylar cut) in Oxford unicompartmental knee arthroplasty to enhance bone cut thickness and to minimize tibial recuts. PATIENTS AND METHODS: Between January 2021 and January 2023, a posterior condyle cut was made before milling in 213 knees in 152 patients (conventional group), while the pre-milling technique was used in 198 knees in 140 patients (pre-milling group). The thickness of the posterior condyle and the rate of tibial recuts were compared between the groups. RESULTS: The bone cut thickness was thinner in the conventional group than in the pre-milling group in small-size (4.7 mm ± 0.6 mm and 5.0 mm ± 0.6 mm, P = 0.0001) and in medium-size (5.1 mm ± 0.5 mm and 5.4 mm ± 0.5 mm, 0.0001) femoral components, whereas there was no difference in large-size femoral components. However, the thickness was still less than the component thickness (5.17 mm for small, 5.57 mm for medium and 6.17 mm for large) in both groups. Tibial recuts were more prevalent in the conventional group than in the pre-milling group (14 knees, 7%, 3 knees 2%, P = 0.002). CONCLUSIONS: The pre-milling technique was found to increase the bone cut thickness in small and medium femoral components, reducing the need for tibial recuts. Further research is warranted to optimize the pre-milling technique and to investigate its long-term impact on patient outcomes.

Propensity of the tight mid-flexion and loose flexion gap despite the adjustment of extension and flexion gaps in Oxford unicompartmental knee arthroplasty: retrospective study.

PURPOSE: A well-balanced joint gap is necessary in Oxford unicompartmental knee arthroplasty (OUKA) to prevent mobile-bearing dislocation. While the gaps between 20° (extension) and 100° (flexion) are precisely adjusted using the incremental mill system, there has been insufficient evaluation of gaps in other angles. We hypothesized that the gap is not always the same in other angles. This retrospective study aimed to evaluate the gap in full-extension (0°), mid-flexion (60°) and deep flexion (130°) for comparison with those in extension and flexion gaps. METHODS: We evaluated 119 knees in 83 patients (51 females, 31 males, aged 71.9 years). The full-extension and mid-flexion gaps were compared with the extension gap, and the deep flexion gap was contrasted with the flexion gap. Each gap was classified into isometric, tight or loose, for evaluation of contributing factors. RESULTS: Although the full-extension gap tended to be isometric (45%), the mid-flexion tended to be tight (48%), whereas the deep-flexion was loose in most knees (84%) (P = 0.002). The tight mid-flexion and loose deep flexion gap pattern accounted for 44% of the total knees, especially so with smaller femoral components (P = 0.004). CONCLUSION: Our results highlight the propensity of tight mid-flexion and loose flexion gap despite the adjustment of extension and flexion gaps in OUKA. Although the effect of such a minor gap imbalance is still unknown, the pattern was more prevalent in patients with smaller-sized femoral components. Use of a larger femoral component may equalize the gap throughout the motion arc.

Antisense oligonucleotides ameliorate kidney dysfunction in podocyte-specific APOL1 risk variant mice.

Coding variants (named G1 and G2) in Apolipoprotein L1 (APOL1) can explain most excess risk of kidney disease observed in African American individuals. It has been proposed that risk variant APOL1 dose, such as increased risk variant APOL1 level serves as a trigger (second hit) for disease development. The goal of this study was to determine whether lowering risk variant APOL1 levels protects from disease development in a podocyte-specific transgenic mouse disease model. We administered antisense oligonucleotides (ASO) targeting APOL1 to podocyte-specific G2APOL1 mice and observed efficient reduction of APOL1 levels. APOL1 ASO1, which more efficiently lowered APOL1 transcript levels, protected mice from albuminuria, glomerulosclerosis, tubulointerstitial fibrosis, and renal failure. Administration of APOL1 ASO1 was effective even for established disease in the NEFTA-rtTA/TRE-G2APOL1 (NEFTA/G2APOL1) mice. We observed a strong correlation between APOL1 transcript level and disease severity. We concluded that APOL1 ASO1 may be an effective therapeutic approach for APOL1-associated glomerular disease.

Trans patellar tendon sagittal tibial cut for lateral unicompartmental knee arthroplasty-location of the split- CT simulation study.

BACKGROUND: In lateral unicompartmental knee arthroplasty (UKA), a sagittal cut is often performed through the patellar tendon (PT). Although the approach is likely widely used, it has not been described in detail, especially regarding the site of the split. This study aimed to clarify where the split should be made. METHODS: This single-center retrospective cohort study included 49 consecutive patients and 51 knees with lateral osteoarthritis. Using preoperative computed tomography, we measured the distance from the medial edge of the PT to the intersection of the PT and the sagittal cutting line, defined as a line parallel to the Akagi's line and passing the tip of the lateral tibial spine. RESULTS: The sagittal cut line passed a mean of 45 ± 11% of the patellar tendon width from the PT medial edge. CONCLUSIONS: The tendon split should be made just medial to the center of the PT because it is where the sagittal cut line for lateral UKA passes.

Approximately 41% of knees have a looser gap in full extension than in 20° flexion after Oxford unicompartmental arthroplasty.

INTRODUCTION: In Oxford unicompartmental knee arthroplasty (OUKA), the flexion and extension gaps should be adjusted to prevent mobile-bearing dislocation. The extension gap is recommended to be evaluated in the 20° flexion position to avoid underestimation due to tension of the posterior capsule. However, we have become aware of a looser gap in full extension than in 20° flexion in some instances. MATERIALS AND METHODS: We retrospectively investigated 83 knees in 60 patients who underwent OUKA between January and June 2020. During surgery, the extension gaps were measured in both full extension and 20° flexion. The knees were classified into two groups: the gap was looser in full extension (0° group), and the gap was equal or looser in 20° flexion than in full extension (20° group). The hip-knee-ankle angle (HKAA), the lateral distal femoral angle (LDFA), the medial proximal tibia angle (MPTA), the posterior tibial slope angle (PTSA), and the last spigot size were also measured and compared between the groups. RESULTS: There was looseness in approximately 41% of knees (34 out of 83 knees) in full extension. In the knees in the 0° group, the last spigot size was significantly smaller (median 1 and 2, P < 0.01). However, there were no significant differences in the HKAA, MPTA, LDFA or PTSA between the groups. CONCLUSIONS: Approximately 41% of knees have a looser gap in full extension than in 20° flexion after OUKA. Further investigation is needed to better understand which extension gap should be used in such cases, and to find the contributing factors in loose full extension gap other than the size of the last spigot.

[Report on COVID-19 infection prevention and control training sessions for care homes provided by Kawaguchi city and comparison with those provided by the local governments in Japan].

Objectives　We compared COVID-19 prevention and control information provided to care homes (CHs) by the Kawaguchi City public health center (PHC), which utilizes our precedent advice on nfection, with the information from several local governments (LGs) in Japan. This study aimed to highlight the role of LG-associated doctors in providing information to CHs, utilizing their precedent advice on infection control in CHs and medical facilities. This study analyzed the sector and type of information the LGs should provide to CHs to prevent and control COVID-19.Methods　We compared training sessions on COVID-19 prevention and control information provided to CHs by the Kawaguchi City PHC with training sessions offered by several other LGs in Japan that are available on their websites.Results　The Kawaguchi City PHC has been providing COVID-19 information to CHs when needed, including prevention and control information, through their doctors, utilizing our precedent advice on infection control, management of health conditions of staff and residents, and early detection of COVID-19. In contrast, 68 LGs announced that they have provided training sessions to CHs for the prevention and control of COVID-19 through their official homepages from March to September 2022. These training sessions involved information dissemination by infection control specialist nurses (42.6%), clinic or hospital doctors (32.4%), infection control specialist doctors (11.8%), and staff from LG headquarters, PHC, or LG-associated doctors (51.5%). Among the 68 LGs, 41 provided information that included hand hygiene (95.1%), personal protective equipment (92.7%), proper ventilation (51.2%), and management of staff (90.2%) and resident (58.5%) health conditions. Furthermore, Kawaguchi City PHC and several LGs provided information for the early detection of COVID-19.Conclusion　We suggest that LGs provide COVID-19 training sessions conducted by LG doctors that include management of staff and resident health conditions, provision of early detection information, and utilization of precedent advice on infection in CHs and medical facilities.

[Dedifferentiated Liposarcoma Originated from Small Bowel Mesentery Resected under Laparoscopic Surgery-A Case Report].

A 74-year-old woman with severe anemia was presented to our hospital to investigate the cause of the disease. Under investigation, submucosal tumor in the small intestine was suspected. We performed the laparoscopic surgery for resection. The pathological diagnosis was dedifferentiated liposarcoma originated from the small bowel mesentery.

Anomalous Epithelial Variations and Ectopic Inflammatory Response in Chronic Obstructive Pulmonary Disease.

Phenotypic alterations in the lung epithelium have been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, but the precise mechanisms orchestrating this persistent inflammatory process remain unknown because of the complexity of lung parenchymal and mesenchymal architecture. To identify cell type-specific mechanisms and cell-cell interactions among the multiple lung resident cell types and inflammatory cells that contribute to COPD progression, we profiled 57,918 cells from lungs of patients with COPD, smokers without COPD, and never-smokers using single-cell RNA sequencing technology. We predicted pseudotime of cell differentiation and cell-to-cell interaction networks in COPD. Although epithelial components in never-smokers were relatively uniform, smoker groups represent extensive heterogeneity in epithelial cells, particularly in alveolar type 2 (AT2) clusters. Among AT2 cells, which are generally regarded as alveolar progenitors, we identified a unique subset that increased in patients with COPD and specifically expressed a series of chemokines including CXCL1 and CXCL8. A trajectory analysis revealed that the inflammatory AT2 cell subpopulation followed a unique differentiation path, and a prediction model of cell-to-cell interactions inferred significantly increased intercellular networks of inflammatory AT2 cells. Our results identify previously unidentified cell subsets and provide an insight into the biological and clinical characteristics of COPD pathogenesis.

Stemness and immune evasion conferred by the TDO2-AHR pathway are associated with liver metastasis of colon cancer.

The aryl hydrocarbon receptor (AHR) pathway modulates the immune system in response to kynurenine, an endogenous tryptophan metabolite. IDO1 and TDO2 catalyze kynurenine production, which promotes cancer progression by compromising host immunosurveillance. However, it is unclear whether the AHR activation regulates the malignant traits of cancer such as metastatic capability or cancer stemness. Here, we carried out systematic analyses of metabolites in patient-derived colorectal cancer spheroids and identified high levels of kynurenine and TDO2 that were positively associated with liver metastasis. In a mouse colon cancer model, TDO2 expression substantially enhanced liver metastasis, induced AHR-mediated PD-L1 transactivation, and dampened immune responses; these changes were all abolished by PD-L1 knockout. In patient-derived cancer spheroids, TDO2 or AHR activity was required for not only the expression of PD-L1, but also for cancer stem cell (CSC)-related characteristics and Wnt signaling. TDO2 was coexpressed with both PD-L1 and nuclear ß-catenin in colon xenograft tumors, and the coexpression of TDO2 and PD-L1 was observed in clinical colon cancer specimens. Thus, our data indicate that the activation of the TDO2-kynurenine-AHR pathway facilitates liver metastasis of colon cancer via PD-L1-mediated immune evasion and maintenance of stemness.

NF-κB suppression synergizes with E7386, an inhibitor of CBP/ß-catenin interaction, to block proliferation of patient-derived colon cancer spheroids.

Dysregulated activation of the WNT/ß-catenin signaling pathway is essential for the initiation and development of various cancers. E7386, a small-molecule compound, attenuates WNT signaling by blocking the interaction between ß-catenin and CREB-binding protein (CBP); hence, it is regarded as a therapeutic candidate for cancers with activated WNT signaling. In the present study, we evaluated the biological characteristics associated with E7386 sensitivity by using a panel of patient-derived colon cancer spheroids. An integrative approach that combined E7386 sensitivity and gene expression profiles revealed that the resistance of the cancer spheroids to E7386 was associated with the activation of the NF-κB pathway. NF-κB pathway inhibitors acted synergistically with E7386 to block proliferation and induce cell cycle arrest in E7386-resistant spheroids. These findings suggest a possibility that a combination of E7386 and NF-κB inhibition may effectively block the proliferation of a subset of colon cancer cells.

Mitochondrial dynamics and degradation in the oleaginous yeast Lipomyces starkeyi.

Emerging evidence implicates the vital role of mitochondria in lipid consumption and storage, highlighting the intimate link between energy production and saving. Although formation of giant lipid droplets, which is the key hallmark of the oleaginous yeast Lipomyces starkeyi, appears to be regulated in response to changes in mitochondrial shape and metabolism, technical limitations of genetic manipulation have become an obstacle to uncover the mitochondrial behavior in this nonconventional yeast. Here, we established an L. starkeyi strain stably expressing a fluorescent marker for monitoring mitochondrial morphology and degradation and found that mitochondria are mostly fragmented in L. starkeyi cells under fermentable, nonfermentable, and nitrogen depletion conditions. Notably, a fraction of mitochondria-specific fluorescent signals was localized to the vacuole, a lytic organelle in yeast, indicating degradation of mitochondria in those cells. This possible catabolic event was more predominant in cells under nutrient-poor conditions than that in cells under nutrient-rich conditions, concomitantly with lipid droplet formation. Collectively, our studies provide a new tool to investigate mitochondrial dynamics in L. starkeyi and decipher the potential role of mitochondrial degradation in lipid metabolism.

Postoperative Maximal Aortic Diameter is a Significant Predictor of Dilation of the Residual Dissected Aorta after Aortic Replacement for Acute Debakey Type I Aortic Dissection.

BACKGROUND: This study investigated the impact of aortic diameter on late aortic dilation of the residual dissected aorta after tear-oriented aortic replacement for acute DeBakey type I aortic dissection. METHODS: Of 133 patients who underwent aortic replacement for acute DeBakey type I/II aortic dissection between 2008 and 2019, 45 patients with a residual dissected aorta after surgery for acute DeBakey type I aortic dissection and who underwent computed tomography at predischarge and after 1 year were retrospectively assessed. The aortic diameter and false lumen area were measured at 3 levels: the maximal aortic site, seventh thoracic vertebra, and celiac axis. Multivariable Cox regression analysis was employed to identify the predictors of late aortic dilation, defined as an aortic growth rate of ≥5 mm/year or a maximal aortic diameter of ≥55 mm. RESULTS: During a median follow-up of 75 [range: 13-152] months, 6 patients (5 men; mean age: 57 ± 14 years) experienced aortic dilation. All 6 patients had the maximal aortic diameter between the distal aortic arch and seventh thoracic vertebra level at the last computed tomography. Multivariable Cox regression analysis showed that the predischarge maximal aortic diameter was an independent determinant of late aortic dilation (hazard ratio: 2.28/mm, 95% confidence interval: 1.10-5.86). CONCLUSIONS: Predischarge maximal aortic diameter is a significant predictor of late aortic dilation in patients with a residual dissected aorta after tear-oriented surgical repair of acute DeBakey type I aortic dissection.

The physiological and pathophysiological roles of carbohydrate response element binding protein in the kidney.

Glucose is not only the energy fuel for most cells, but also the signaling molecule which affects gene expression via carbohydrate response element binding protein (ChREBP), a Mondo family transcription factor. In response to high glucose conditions, ChREBP regulates glycolytic and lipogenic genes by binding to carbohydrate response elements (ChoRE) in the regulatory region of its target genes, thus elucidating the role of ChREBP for converting excessively ingested carbohydrates to fatty acids as an energy storage in lipogenic tissues such as the liver and adipose tissue. While the pathophysiological roles of ChREBP for fatty liver and obesity in these tissues are well known, much of the physiological and pathophysiological roles of ChREBP in other tissues such as the kidney remains unclear despite its high levels of expression in them. This review will thus highlight the roles of ChREBP in the kidney and briefly introduce the latest research results that have been reported so far.

Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells.

Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.

Single-cell DNA and RNA sequencing reveals the dynamics of intra-tumor heterogeneity in a colorectal cancer model.

BACKGROUND: Intra-tumor heterogeneity (ITH) encompasses cellular differences in tumors and is related to clinical outcomes such as drug resistance. However, little is known about the dynamics of ITH, owing to the lack of time-series analysis at the single-cell level. Mouse models that recapitulate cancer development are useful for controlled serial time sampling. RESULTS: We performed single-cell exome and transcriptome sequencing of 200 cells to investigate how ITH is generated in a mouse colorectal cancer model. In the model, a single normal intestinal cell is grown into organoids that mimic the intestinal crypt structure. Upon RNAi-mediated downregulation of a tumor suppressor gene APC, the transduced organoids were serially transplanted into mice to allow exposure to in vivo microenvironments, which play relevant roles in cancer development. The ITH of the transcriptome increased after the transplantation, while that of the exome decreased. Mutations generated during organoid culture did not greatly change at the bulk-cell level upon the transplantation. The RNA ITH increase was due to the emergence of new transcriptional subpopulations. In contrast to the initial cells expressing mesenchymal-marker genes, new subpopulations repressed these genes after the transplantation. Analyses of colorectal cancer data from The Cancer Genome Atlas revealed a high proportion of metastatic cases in human subjects with expression patterns similar to the new cell subpopulations in mouse. These results suggest that the birth of transcriptional subpopulations may be a key for adaptation to drastic micro-environmental changes when cancer cells have sufficient genetic alterations at later tumor stages. CONCLUSIONS: This study revealed an evolutionary dynamics of single-cell RNA and DNA heterogeneity in tumor progression, giving insights into the mesenchymal-epithelial transformation of tumor cells at metastasis in colorectal cancer.

Short distance from the keel to the posterior tibial cortex is associated with fracture after cementless Oxford UKA in Asian patients.

PURPOSE: Tibial plateau fractures are serious complications of Oxford mobile-bearing unicompartmental knee arthroplasty (OUKA). This study examined where the fracture lines arises and evaluated the keel-cortex distances (KCDs) using three-dimensional computed tomography (3D-CT) and the effects of technical error (assessed by tibial component positions) and proximal tibial morphology on the KCDs. METHODS: This retrospective study included 217 OUKAs with cementless tibial components. Fifteen patients had tibial fractures after surgery. Anterior and posterior KCDs and fracture line origins were assessed using 3D-CT postoperatively. Proximal tibial morphology was assessed using the medial eminence line (MEL), which runs parallel to the tibial axis and passes through the tip of the medial intercondylar eminence of the tibia on long-leg anteroposterior radiograph. Knees had overhanging medial tibial condyle if the MEL passed medially to the medial tibial cortex. KCDs were compared between patients with/without fractures. Tibial component positions were evaluated, considering effects of tibial morphologies and component positions on fracture prevalence and KCDs. RESULTS: Fracture lines were found between the keel and posterior cortex in 12/15 patients. Posterior KCDs were significantly shorter in patients with fractures than in patients without (2.7 ± 1.6 mm vs 5.2 ± 1.7 mm, P < 0.001). Patients with medial overhanging condyles were more likely to have fracture (10/51 vs 5/166, P < 0.001) and had significantly shorter posterior KCD than those without (3.6 ± 1.5 mm vs 5.5 ± 1.8 mm, P < 0.001). Patients with tibial component that was set too medial, low, and valgus had higher rates of fracture than those without (7/39 vs 8/178, P = 0.008). Medial (r = 0.30, P < 0.001), low (r = -0.33, P < 0.001), and valgus implantations (r = 0.35, P < 0.001) of tibial components were related to shorter posterior KCDs. CONCLUSION: Short posterior KCD after OUKA is a risk factor for postoperative tibial fracture. Patients with either malposition of the tibial component (too medial, low, and valgus) and/or a medial overhanging condyle exhibit a shorter distance of posterior KCD and higher rate of fracture. LEVEL OF EVIDENCE: Level III.