Novel risk factors for craniofacial microsomia and assessment of their utility in clinic diagnosis.

Craniofacial microsomia (CFM, OMIM%164 210) is one of the most common congenital facial abnormalities worldwide, but it's genetic risk factors and environmental threats are poorly investigated, as well as their interaction, making the diagnosis and prenatal screening of CFM impossible. We perform a comprehensive association study on the largest CFM cohort of 6074 samples. We identify 15 significant (P < 5 × 10-8) associated genomic loci (including eight previously reported) and decipher 107 candidates based on multi-omics data. Gene Ontology term enrichment found that these candidates are mainly enriched in neural crest cell (NCC) development and hypoxic environment. Single-cell RNA-seq data of mouse embryo demonstrate that nine of them show dramatic expression change during early cranial NCC development whose dysplasia is involved in pathogeny of CFM. Furthermore, we construct a well-performed CFM risk-predicting model based on polygenic risk score (PRS) method and estimate seven environmental risk factors that interacting with PRS. Single-nucleotide polymorphism-based PRS is significantly associated with CFM [P = 7.22 × 10-58, odds ratio = 3.15, 95% confidence interval (CI) 2.74-3.63], and the top fifth percentile has a 6.8-fold CFM risk comparing with the 10th percentile. Father's smoking increases CFM risk as evidenced by interaction parameter of -0.324 (95% CI -0.578 to -0.070, P = 0.011) with PRS. In conclusion, the newly identified risk loci will significantly improve our understandings of genetics contribution to CFM. The risk prediction model is promising for CFM prediction, and father's smoking is a key environmental risk factor for CFM through interacting with genetic factors.

Progress on the regulation of neural crest and the genetics in craniofacial development.

The craniofacial features endow vertebrates with unparalleled evolutionary advantages. The craniofacial is composed of bone, cartilage, nerves, and connective tissues mainly developed from cranial neural crest cells (cNCCs). These tissues form complex organs which enable vertebrates to have powerful neural and sensory systems. NCCs are groups of migratory and pluripotent cells that are specific to vertebrates. The specification, premigration and migration, proliferation, and fate determination of the NCCs are precisely and sequentially controlled by gene regulatory networks, to ensure the ordered and accurate development of the craniofacial region. The craniofacial region represents a combined set of highly heritable phenotypes, which could be illustrated by the inherited facial features between relatives but perceptible differences among non-relatives. Such phenomena are termed heredity and variation, which are in accordance with the precision and plasticity of cNCCs gene regulatory network, respectively. Evidence has shown that genetic variations within the regulatory network alter the proliferation and differentiation of NCCs within a tolerable range, while deleterious mutations will lead to craniofacial malformations. In this review, we first summarize the development procedure of NCCs and their gene regulatory networks and then provide an overview on the genetic basis of the facial morphology and malformations. This review will benefit the understanding of craniofacial development and the prevention of craniofacial diseases.

Research progress on neural crest cells and neurocristopathies and its pathogenesis.

Neural crest cells (NCCs) are multipotent progenitor cells unique to vertebrates, and they have the ability to differentiate into a variety of cells, such as chondrocytes, neurons, and melanocytes. The formation, migration, and differentiation of NCCs are tightly regulated, and the disruption of NCC development results in abnormal embryo development. Neurocristopathies (NCPs) refer to a group of diseases that develop in response to abnormal development of NCCs. NCPs are of various types and exhibit complex phenotypes, which can affect many parts of the human body, such as the craniofacial structure, heart, intestine, and skin. NCPs negatively impact the physical function and mental health of the affected patients. NCPs account for one third of the defects in children with birth defects. Genetic factors are the main risk factors for NCPs, but environmental factors and abnormal gene-environment interactions can also lead to the development of NCPs. In this review, we introduce NCCs, NCPs, and their pathogenesis, so as to provide a reference point for a systematic understanding of NCPs and NCC development, and to provide scientific support for understanding the etiology of NCPs and their effective prevention and control.

Serum neurofilament light chain and glial fibrillary acidic protein in AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and multiple sclerosis: A cohort study.

We investigated the serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels in a cohort of Chinese patients with neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) in relation to clinical disease course and treatment. sNfL and sGFAP levels were determined by ultrasensitive single molecule array (Simoa) assay in patients with NMOSD (n = 102) and MS (n = 98) and healthy controls (HCs; n = 84). Notably, 13 patients with NMOSD and 27 patients with MS were enrolled in the 1-year follow-up cohort. Levels were compared with data such as clinical course, disease duration, Expanded Disability Status Scale (EDSS) score, and lesions on MRI. Higher levels of sNfL and sGFAP were found in subjects with NMOSD and MS than in HCs (sNfL, median 12.11, 17.5 vs. 8.88 pg/ml, p < .05; sGFAP, median 130.2, 160.4 vs. 80.01 pg/ml, p < .05). Moreover, sNfL levels were higher in the relapse phase of MS than in the relapse phase of NMOSD (30.02 vs. 14.57 pg/ml, p < .05); sGFAP levels were higher in the remission phase of MS than in the remission phase of NMOSD (159.8 vs. 124.5 pg/ml, p < .01). A higher sGFAP/sNfL quotient at relapse differentiated NMOSD from MS. Multivariate analyses indicated that sGFAP levels were associated with the EDSS score in NMOSD (p < .05). At the 1-year follow-up, sNfL and sGFAP levels were both decreased in NMOSD patients in remission, while only sNfL levels were decreased in MS patients in remission. sGFAP and sNfL are potential blood biomarkers for diagnosing and monitoring NMOSD and MS.

NAPG mutation in family members with hereditary hemorrhagic telangiectasia in China.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations in the skin and mucous membranes. We enrolled a large pedigree comprising 32 living members, and screened for mutations responsible for HHT. METHODS: We performed whole-exome sequencing to identify novel mutations in the pedigree after excluding three previously reported HHT-related genes using Sanger sequencing. We then performed in silico functional analysis of candidate mutations that were obtained using a variant filtering strategy to identify mutations responsible for HHT. RESULTS: After screening the HHT-related genes, activin A receptor-like type 1 (ACVRL1), endoglin (ENG), and SMAD family member 4 (SMAD4), we did not detect any co-segregated mutations in this pedigree. Whole-exome sequencing analysis of 7 members and Sanger sequencing analysis of 16 additional members identified a mutation (c.784A > G) in the NSF attachment protein gamma (NAPG) gene that co-segregated with the disease. Functional prediction showed that the mutation was deleterious and might change the conformational stability of the NAPG protein. CONCLUSIONS: NAPG c.784A > G may potentially lead to HHT. These results expand the current understanding of the genetic contributions to HHT pathogenesis.

Epidemiological Analysis and the Nomogram for Possible Risk Factors for Severe Microtia.

BACKGROUND: Microtia is a severe congenital malformation of the external ear. This study aimed to explore the epidemiologic characteristics and the possible risk factors in patients with severe microtia in China, and integrate significant variables into a predictive nomogram. METHODS: A total of 965 patients with microtia were included. This retrospective case study was conducted from July 2014 to July 2019 at Plastic Surgery Hospital in China. The detailed questionnaires concerning potential risk factors were completed and data were gathered. Chi-Square and Fisher tests were used to analyze the variables, and a multivariate logistic regression model was used to select variables related to severe microtia, and then construct a nomogram. The nomogram model was evaluated by the concordance index (C-index), calibration plot, and receiver operating characteristics (ROCs) curve. Bootstraps with 1000 resamples were applied to these analyses. RESULTS: Of the 965 microtia patients, 629 (65.2%) were male and 867 (89.8%) were sporadic. The cases were observed more commonly in unilateral (83.1%) and right-sided (52.0%). And multiple malformations were observed in 392 (40.6%) cases. Multivariate logistic regression analysis showed that maternal age, miscarriage frequency, virus infection, anemia, using progesterone, paternal alcohol intake, and topography of living areas were associated with a higher risk of severe microtia. All the significant variables were combined into a predictive nomogram (C-index = 0.755,95% CI = 0.703-0.807). Higher prediction accuracy (adjusted C-index = 0.749) was further verified via bootstrap validation. The calibration plot showed good performance, and the ROCs curve analysis demonstrated high sensitivity and specificity. CONCLUSIONS: Most microtia patients are male, sporadic, and accompanied by other malformations, which are similar to the phenotypic analysis results of other studies. A nomogram predicting severe microtia was constructed to provide scientific guidance for individualized prevention in clinical practice.

A Novel IRF6 Variant Detected in a Family With Nonsyndromic Cleft Lip and Palate by Whole Exome Sequencing.

ABSTRACT: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common congenital craniofacial malformation, and its harmful effects on affected individuals and families are apparent. The causative genes and their mechanisms are not completely clear, although several studies have been conducted. Accordingly, in the present study, we recruited a Han Chinese family with hereditary NSCL/P to explore the possible causative variants of this disease using whole exome sequencing. Bioinformatics screening and analysis, mutation function prediction, species conservation analysis, and homology protein modeling were used to identify the variants and evaluate their influence. A mutation in the interferon regulatory factor 6 (IRF6) gene (c.961C>T; p.Val321Met) was detected as a candidate causative variant and predicted to be deleterious. The codon was found to be conserved in many species, and the residue change caused by this mutation changed the structure of IRF6 to a certain degree. The findings suggest that this IRF6 variant is probably the pathogenic cause of NSCL/P in this family. Our results further provide evidence that IRF6 variants play a role in the etiology of NSCL/P.

Discovery of susceptibility loci associated with tuberculosis in Han Chinese.

Genome-wide association studies (GWASs) have revealed the worldwide heterogeneity of genetic factors in tuberculosis (TB) susceptibility. Despite having the third highest global TB burden, no TB-related GWAS has been performed in China. Here, we performed the first three-stage GWAS on TB in the Han Chinese population. In the stage 1 (discovery stage), after quality control, 691 388 SNPs present in 972 TB patients and 1537 controls were retained. After replication on an additional 3460 TB patients and 4862 controls (stages 2 and 3), we identified three significant loci associated with TB, the most significant of which was rs4240897 (logistic regression P = 1.41 × 10-11, odds ratio = 0.79). The aforementioned three SNPs were harbored by MFN2, RGS12 and human leukocyte antigen class II beta chain paralogue encoding genes, all of which are candidate immune genes associated with TB. Our findings provide new insight into the genetic background of TB in the Han Chinese population.

Interaction between interferon regulatory factor 6 and glycine receptor beta shows a protective effect on developing nonsyndromic cleft lip with or without cleft palate in the Han Chinese population.

Single-nucleotide polymorphisms (SNPs) in protein-coding regions of genes which were previously reported to be associated with nonsyndromic cleft lip, with or without palate involvement (NSCL/P), were investigated. Twelve candidate loci [platelet-derived growth factor C (PDGFC), platelet-derived growth factor subunit A (PDGFA), platelet-derived growth factor receptor alpha (PDGFRA), glycine receptor alpha 2 (GLRA2), glycine receptor beta (GLRB), ATP binding cassette subfamily A member 4 (ABCA4), MAF bZIP transcription factor B (MAFB), interferon regulatory factor 6 (IRF6), CCDC26 long non-coding RNA (CCDC26), paired box 7 (PAX7), ventral anterior homeobox 1 (VAX1), and netrin 1 (NTN1)] covering 1.5 Mbp were sequenced in 136 NSCL/P patients and 54 healthy controls. Twenty-five genomic variants identified were further validated in another 400 NSCL/P and 200 controls. Two SNPs in IRF6 showed a protective effect against the development of NSCL/P (rs12405750, OR = 0.54, 95% CI: 0.41-0.69; and rs2235371, OR = 0.55, 95% CI: 0.43-0.71). The missense variant, rs2235371, alters the conserved amino acid valine to isoleucine at codon 274 (V274I). We observed that SNPs at IRF6 (rs2235371 and rs12405750) and GLRB (rs73856838 and rs72685584) show consistent interaction effects. The association between the missense SNP rs2235371 in gene IRF6 and NSCL/P suggests that this SNP may play an important role as a risk factor for NSCL/P in the Han Chinese populations. The marginal signal near 4q31 detected in previous genome-wide association studies might be caused by an interaction between the IRF6 and GLRB genes. This interaction needs to be further validated by experimentation in follow-up studies.

WITHDRAWN: Whole genome sequencing identifies novel NOTCH3 mutations for leukoaraiosis.

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Simultaneous Bilateral Microtia Reconstruction Using Single-Expanded Postauricular Flap Without Skin Grafting.

BACKGROUND: Auricular reconstruction in patients with congenital microtia permits craniofacial balance and harmony, especially in patients with bilateral microtia. However, published techniques usually require skin grafting, which can lead to color mismatch and visible scarring. Some surgeons prefer to reconstruct the auricle of each side separately, which prolongs the complete cycle of surgery and increases suffering of the patient. In this study, we introduce a modified technique using single expanded flaps without skin grafting to achieve simultaneous bilateral auricular reconstruction. METHODS: Between January 2012 and January 2017, a total of 54 patients with bilateral microtia underwent auricular reconstruction with expanded single flaps. Simultaneous bilateral auricular reconstruction was accomplished through 3 surgical stages. In the first stage, bilateral postauricular skin was expanded using 2 kidney-shaped tissue expanders. In the second stage, bilateral rib cartilage was harvested using minimal incisions, allowing 2 modified 3-layer frameworks to be fabricated. Each framework was then inserted into the pocket through the same incision with subsequent closure using 2-layer suture. In the third stage, the reconstructed ears were further trimmed, if necessary, and the lobules and tragus reconstructed. All the patients were followed up for 6 to 24 months. RESULTS: During follow-up, patients were satisfied with surgical outcome in terms of size, shape, location, detailing, and symmetry of the bilateral ears in more than 50 cases. Only 4 demonstrated postoperative complications. No skin necrosis, exposure of cartilage, or infection was observed or postoperative chest deformities. CONCLUSIONS: Simultaneous bilateral auricular reconstruction using single expanded flaps combined with a modified 3-layer cartilage framework is an effective technique for patients with bilateral microtia.

Seasonal Variations in Microtia of Chinese Population.

BACKGROUND: Seasonality of congenital birth defect could help to identify environmental risk factors. Data concerning the seasonality of the prevalence of microtia are little. This article aims to determine whether births of microtia follow a certain pattern. METHODS: Data were obtained from 2669 patients with microtia who were admitted to Second Ear Reconstruction Center of Plastic Surgery Hospital, Chinese Academy of Medical Science from January 2007 to December 2013. The controls consist of all living births from the Obstetric Department of the Haidian Maternal & Child Health Hospital during the same time. Seasonal variations in months of births were analyzed by using χ test. RESULTS: A total of 2669 patients with microtia and 89,273 healthy living newborns were included in this study. Birth time peak of the patients occurred in autumn, especially in November, compared with the nadir in the spring, especially in April (P G 0.05). The birth time peak of male patients occurred in autumn, too, especially in October and November, While the valley occurred in spring (April, too). However, the seasonality in female patients is not so apparent with the peak occurred in the tail of summer and autumn, especially in August, November, and September orderly, while the valley occurred in March. CONCLUSIONS: There is a possible seasonality in birth months and a difference between sexes of patients with microtia in this native Chinese population. This approach could be useful to study the etiology of microtia.

Aesthetic Auricular Reconstruction in Adult Patients with Rib Cartilage Calcification Using a Modified Two-Step Technique.

BACKGROUND: It is very important for congenital microtia patients to achieve better aesthetic appearance, craniofacial balance and mental health through auricular reconstruction. But there are great challenges for plastic surgeons on how to perform this technique in adult patients with tough and rigid rib cartilage because of the different extent of calcification. To lower the harvest of the cartilage and reduce the suffering during the operation, in this study, we report a modified two-step method for adult patients who suffered rib cartilage calcification in auricular reconstruction. METHODS: From January 2012 to January 2018, 89 adult patients (aged from 24 to 50) with cartilage calcification were enrolled and received auricular reconstruction using the modified two-step technique. The whole procedure was performed in two surgical stages. In the first stage, rib cartilages were harvested and modified cartilage frameworks were designed, fabricated and grafted, which included an ear-shaped framework and a C-shaped base part. The ear-shaped framework was inserted into the mastoid region through a W-shaped incision, but the C-shaped base part was embedded subcutaneously in the donor site. In the second stage, the C-shaped base part was transplanted into the mastoid region to elevate the reconstructed ear. A retro-auricular fascia flap and a free skin graft were used to cover the posterior side of the reconstructed ear. RESULTS: The patients were followed for 6 to 24 months. During the follow-up visiting, 80 cases (89%) were satisfied with the outcomes in size, shape, location and details of reconstructed ears. CONCLUSION: Our modified technique is safe and effective for auricular reconstruction, reduces the harvest of cartilage and decreases the suffering as well in adult patients with congenital microtia and rib cartilage calcification. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Turtles as a Possible Reservoir of Nontyphoidal Salmonella in Shanghai, China.

Terrapins and turtles are known to transmit Salmonella to humans. However, little was known about the occurrence of this pathogen in soft-shelled terrapin that is a popular delicacy in Chinese and other East Asian cuisines. We isolated and characterized 82 (24.4%) isolates of Salmonella from 336 fecal samples of soft-shelled terrapins (51 of 172; 29.7%) and pet turtles (31 of 164; 18.9%) in Shanghai. Salmonella Thompson was the most common serotype (17.1%) among others. Many isolates (84.1%) were resistant to multiple antimicrobials (≥3). Molecular analysis of Salmonella Thompson and Salmonella Typhimurium using pulsed-field gel electrophoresis unveiled a close genetic relationship between several human and terrapin isolates. Our results highlight the risk associated with the handling and consumption of turtles and their role in the spread of Salmonella in the human salmonellosis.

The Retrograde Transposition of the Remnant Earlobe in Patients With Low-Set Microtia.

During auricle reconstruction, lobular transposition has become a routine technique applied by most of surgeons. But to some low-set remnant ears, it is difficult to manipulate the conventional lobule transposition method in clinical application. In this article, the authors introduce a method to retrogradely transpose the remnant ear with the the ratio of length:width of the lobular flap being 4-5:1. The lobule transposition could be applied during the first stage of Nagata method or the third stage using expansion method. The authors take the superior part of the remnant ear as the pedicle and make the incision at the middle and inferior parts of the remnant ear to form the lobular flap. Then the inferior lobule is rotated posteriorly and superiorly to cover the rear end of the framework and to form the inferior part of helical rim. The results of the reconstructed auricles are satisfactory with aesthetic natural earlobes and the location of the reconstructed ear is symmetric to the contralateral ear. The authors believe that to the 2% to 5% patients with low-set microtia, this is a good way to make use of remnant ear for the purpose of a real earlobe.

Treatment of postburn ear defect with expanded upper arm flap and consequent expansion without skin grafting.

Total ear reconstruction in the postburn auricle is one of the most challenging procedures for plastic surgeons. Adverse factors associated with these procedures include reduced or damaged blood supply, poor elasticity of scar tissue, increased risk of infection, and the possible destruction of skin, temporoparietal fascia, or retroauricular fascia. In cases where patients are severely burned, free flaps, such as radial forearm flaps, contralateral temporoparietal fascial flaps, or omental flaps, can be used as framework envelopes. In this work, we introduced a novel method of expanded upper arm flap transfer, followed by an expansion method of total ear reconstruction without skin grafting.

Ca2+/calmodulin-mediated desensitization of glutamate receptors shapes plant systemic wound signalling and anti-herbivore defence.

Plants rely on systemic signalling mechanisms to establish whole-body defence in response to insect and nematode attacks. GLUTAMATE RECEPTOR-LIKE (GLR) genes have been implicated in long-distance transmission of wound signals to initiate the accumulation of the defence hormone jasmonate (JA) at undamaged distal sites. The systemic signalling entails the activation of Ca2+-permeable GLR channels by wound-released glutamate, triggering membrane depolarization and cytosolic Ca2+ influx throughout the whole plant. The systemic electrical and calcium signals rapidly dissipate to restore the resting state, partially due to desensitization of the GLR channels. Here we report the discovery of calmodulin-mediated, Ca2+-dependent desensitization of GLR channels, revealing a negative feedback loop in the orchestration of plant systemic wound responses. A CRISPR-engineered GLR3.3 allele with impaired desensitization showed prolonged systemic electrical signalling and Ca2+ waves, leading to enhanced plant defence against herbivores. Moreover, this Ca2+/calmodulin-mediated desensitization of GLR channels is a highly conserved mechanism in plants, providing a potential target for engineering anti-herbivore defence in crops.

Association of SERPINE2 gene with the risk of chronic obstructive pulmonary disease and spirometric phenotypes in northern Han Chinese population.

Chronic obstructive pulmonary disease (COPD) is a complex human disease influenced by multiple genes and environmental factors. The SERPINE2 gene has recently been demonstrated to be associated with COPD onset in a non-East Asian population. In this study, we genotyped 20 single nucleotide polymorphisms (SNPs) in SERPINE2 from 310 cases and 203 controls, all of which belong to the Han from North China. Genotype frequencies were compared between the cases and the controls and analyzed for statistical significance. Two SNPs (rs729631 and rs975278), which are in strong linkage disequilibrium (LD) and locate in block 1 on the LD map of our samples, showed significant association both with the risk of COPD and decline in baseline lung function after Bonferroni correction (P < 0.05). This study provides further evidences for SERPINE2 gene as a COPD susceptible gene, and block 1 of SERPINE2 appears to be the genetic variant region that affects the Han Chinese.

Activation of farnesoid X receptor signaling by geniposidic acid promotes osteogenesis.

BACKGROUND: New targets and strategies are urgently needed for the identification and development of anabolic drugs for osteoporosis. Farnesoid X receptor (FXR) is a promising novel therapeutic target for bone metabolism diseases. Although used clinically, FXR agonists have obvious side effects; therefore, the development of new FXR agonists for the treatment of osteoporosis would be welcomed. Geniposidic acid (GPA) is a bioactive compound extracted from Eucommiae cortex, which is used for treating arthritis, osteoporotic fractures, and hypertension. However, the therapeutic effects of GPA against osteoporosis remain underexplored. PURPOSE: This study aims to reveal the potential osteogenic effects of FXR and to explore the effect of GPA on bone formation, osteoporosis treatment, and FXR signaling. STUDY DESIGN & METHODS: The role of FXR in promoting bone formation was evaluated in Fxr knockout (Fxr-/-) mice and cell models. GPA activation of FXR was evaluated by molecular docking and luciferase reporter gene assays. Thirty female C57BL/6J mice were randomly assigned into a sham operation group (Sham) and four ovariectomized (OVX) groups (n=6 each) and were treated with vehicle or different doses of GPA (25, 50, and 100 mg/kg/day). The therapeutic effect of GPA on osteoporosis was systematically analyzed by performing bone histomorphometry and measuring serum biochemical parameters, and the molecular mechanism was also evaluated. Furthermore, the action of GPA in Fxr-/- mice was evaluated to investigate its dependency on FXR in promoting bone formation and treating osteoporosis. RESULTS: We found that FXR was highly expressed in bone tissues and enriched in osteoblasts. Notably, deletion of FXR significantly reduced the bone formation rate and bone mass of the Fxr-/- mice compared with wild-type mice. Furthermore, using a high throughput drug screening strategy based on fluorescent reporter genes, we found that GPA functions as a natural agonist of FXR. We confirmed the activities of GPA on FXR activation and osteogenesis in both osteoblast differentiation models and OVX-induced osteoporosis models. We revealed that GPA strongly promotes bone formation by activating FXR/RUNX2 signaling. Moreover, the osteoporotic therapeutic effect of GPA was abolished in Fxr-/- mice. CONCLUSION: This study demonstrated that FXR is a promising target for treating osteoporosis and that GPA promotes bone formation in OVX-induced osteoporosis by activating FXR signaling. These findings provide novel insight into the mechanism by which GPA promotes bone formation and more evidence for its application in the treatment of osteoporosis.

Generation of functional oligopeptides that promote osteogenesis based on unsupervised deep learning of protein IDRs.

Deep learning (DL) is currently revolutionizing peptide drug development due to both computational advances and the substantial recent expansion of digitized biological data. However, progress in oligopeptide drug development has been limited, likely due to the lack of suitable datasets and difficulty in identifying informative features to use as inputs for DL models. Here, we utilized an unsupervised deep learning model to learn a semantic pattern based on the intrinsically disordered regions of ~171 known osteogenic proteins. Subsequently, oligopeptides were generated from this semantic pattern based on Monte Carlo simulation, followed by in vivo functional characterization. A five amino acid oligopeptide (AIB5P) had strong bone-formation-promoting effects, as determined in multiple mouse models (e.g., osteoporosis, fracture, and osseointegration of implants). Mechanistically, we showed that AIB5P promotes osteogenesis by binding to the integrin α5 subunit and thereby activating FAK signaling. In summary, we successfully established an oligopeptide discovery strategy based on a DL model and demonstrated its utility from cytological screening to animal experimental verification.