Genome wide association study in Swedish Labrador retrievers identifies genetic loci associated with hip dysplasia and body weight.

Genome wide association studies (GWAS) have been utilized to identify genetic risk loci associated with both simple and complex inherited disorders. Here, we performed a GWAS in Labrador retrievers to identify genetic loci associated with hip dysplasia and body weight. Hip dysplasia scores were available for 209 genotyped dogs. We identified a significantly associated locus for hip dysplasia on chromosome 24, with three equally associated SNPs (p = 4.3 × 10-7) in complete linkage disequilibrium located within NDRG3, a gene which in humans has been shown to be differentially expressed in osteoarthritic joint cartilage. Body weight, available for 85 female dogs, was used as phenotype for a second analysis. We identified two significantly associated loci on chromosome 10 (p = 4.5 × 10-7) and chromosome 31 (p = 2.5 × 10-6). The most associated SNPs within these loci were located within the introns of the PRKCE and CADM2 genes, respectively. PRKCE has been shown to play a role in regulation of adipogenesis whilst CADM2 has been associated with body weight in multiple human GWAS. In summary, we identified credible candidate loci explaining part of the genetic inheritance for hip dysplasia and body weight in Labrador retrievers with strong candidate genes in each locus previously implicated in the phenotypes investigated.

Identification of A Novel Variant of Filamin A Destroying the Attraction Between Benzene Rings and Sulfhydryl in Developmental Dysplasia of the Hip.

Developmental dysplasia of the hip (DDH), characterized by acetabular deformity that manifests from loose ligaments to complete dislocation of the hip, can cause notable pain and dysfunction and lead to hip dislocation, secondary fractures, scoliosis, and osteoarthritis of hip. Variants in FLNA may produce a spectrum of malformations in multiple organs, especially the skeleton. This study aimed to identify the genetic etiologies of DDH patients and provide genetic testing information for further diagnosis and treatment of DDH. We recruited a Chinese woman with DDH and her family members. Whole-exome sequencing was used to identify the patient's genetic etiologies. Protein models were used to analyze the pathogenic mechanism of the identified variants. A novel variant (c.3493T>G, p.C1165G) of FLNA was detected. The structural models of the mutant FLNA protein indicated that the variant would lose its sulfhydryl side chain and destroy the attraction between benzene rings and sulfhydryl. We reported a novel variant (c.3493T>G, p.C1165G) of FLNA in a Chinese woman with DDH. Our research outcome enriches the gene pool for hip dysplasia and emphasizes the pathogenicity of sulfhydryl side chain disruption in FLNA.

Developmental dysplasia of the hip: A systematic review of susceptibility genes and epigenetics.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a complex developmental deformity whose pathogenesis and susceptibility-related genes have yet to be elucidated. This systematic review summarizes the current literature on DDH-related gene mutations, animal model experiments, and epigenetic changes in DDH. METHODS: We performed a comprehensive search of relevant documents in the Medline, Scopus, Cochrane, and ScienceDirect databases covering the period from October 1991 to October 2021. We analyzed basic information on the included studies and summarized the DDH-related mutation sites, animal model experiments, and epigenetic changes associated with DDH. RESULTS: A total of 63 studies were included in the analysis, of which 54 dealt with the detection of gene mutations, 7 presented details of animal experiments, and 6 were epigenetic studies. No genetic mutations were clearly related to the pathogenesis of DDH, including the most frequently studied genes on chromosomes 1, 17, and 20. Most gene-related studies were performed in Han Chinese or North American populations, and the quality of these studies was medium or low. GDF5 was examined in the greatest number of studies, and mutation sites with odds ratios > 10 were located on chromosomes 3, 9, and 13. Six mutations were found in animal experiments (i.e., CX3CR1, GDF5, PAPPA2, TENM3, UFSP2, and WISP3). Epigenetics research on DDH has focused on GDF5 promoter methylation, three microRNAs (miRNAs), and long noncoding RNAs. In addition, there was also a genetic test for miRNA and mRNA sequencing. CONCLUSIONS: DDH is a complex joint deformity with a considerable genetic component whose early diagnosis is significant for preventing disease. At present, no genes clearly involved in the pathogenesis of DDH have been identified. Research on mutations associated with this condition is progressing in the direction of in vivo experiments in animal models to identify DDH susceptibility genes and epigenetics analyses to provide novel insights into its pathogenesis. In the future, genetic profiling may improve matters.

Whole exome sequencing of 28 families of Danish descent reveals novel candidate genes and pathways in developmental dysplasia of the hip.

Developmental dysplasia of the hip (DDH) is a common condition involving instability of the hip with multifactorial etiology. Early diagnosis and treatment are critical as undetected DDH is an important cause of long-term hip complications. Better diagnostics may be achieved through genetic methods, especially for patients with positive family history. Several candidate genes have been reported but the exact molecular etiology of the disease is yet unknown. In the present study, we performed whole exome sequencing of DDH patients from 28 families with at least two affected first-degree relatives. Four genes previously not associated with DDH (METTL21B, DIS3L2, PPP6R2, and TM4SF19) were identified with the same variants shared among affected family members, in more than two families. Among known association genes, we found damaging variants in DACH1, MYH10, NOTCH2, TBX4, EVC2, OTOG, and SHC3. Mutational burden analysis across the families identified 322 candidate genes, and enriched pathways include the extracellular matrix, cytoskeleton, ion-binding, and detection of mechanical stimulus. Taken altogether, our data suggest a polygenic mode of inheritance for DDH, and we propose that an impaired transduction of the mechanical stimulus is involved in the etiopathological mechanism. Our findings refine our current understanding of candidate causal genes in DDH, and provide a foundation for downstream functional studies.

Identification of KANSL1 as a novel pathogenic gene for developmental dysplasia of the hip.

Developmental dysplasia of the hip (DDH) is a common anomaly leading to adult osteoarthritis. Environmental and genetic factors contribute to DDH, but its exact genetic mechanism is unclear. In this study, we used whole exome sequencing to identify the causative gene of a DDH pedigree. A rare missense variant in KANSL1 (c.C767T; p.S256F) was identified as the pathogenic cause of DDH. Subsequent mutation screening showed another missense variant in 1 of 200 sporadic patients. Kansl1-mutated mice showed reduced chondrocytes in the acetabulum and a decrease in the cartilage matrix, which may be DDH phenotype-related abnormalities. Furthermore, functional studies showed that cell proliferation was delayed and Mmp13 expression was abnormally upregulated in chondrocytes differentiated from Kansl1 mutant mouse embryonic stem cells. In conclusion, our findings suggest that KANSL1 is a novel pathogenic gene for DDH. The identification of KANSL1 variants has great diagnostic value for identifying individuals with DDH. KEY MESSAGES: Developmental dysplasia of the hip (DDH) is a common anomaly causing adult osteoarthritis. Environmental and genetic factors contribute to DDH, but its exact genetic mechanism is unclear. Using high-throughput whole exome sequencing, we found a novel variant in KANSL1 that was co-inherited by all severely affected individuals diagnosed with DDH from a three-generation family. Further analysis revealed that a Kansl1 variant in mice reduced the number of chondrocytes and decreased cartilage matrix, and mouse embryonic stem differentiation assay showed cartilage defects. These findings indicate a direct association between KANSL1 and hip development, expanding the pathogenic gene spectrum in DDH and providing insight into potential new targets for diagnosing and treating hip dysplasia.

Establishment of pediatric developmental dysplasia of the hip biobank: Shanghai children's hospital experience.

Developmental dysplasia of the hip (DDH) is a debilitating condition that affects 1-7% of newborns. Children with DDH, not treated early and effectively, will easily lead to disability. A better understanding of the biology of DDH is critical to the development of prognostic biomarkers and novel therapies. The purpose of this study was to establish a biobank of DDH genetic resources, to facilitate clinical and basic scientific research. The biological specimen and clinical data of DDH were collected in Shanghai Children's Hospital from 2014 to 2021. The collection of blood samples was performed at definitive diagnosis and review, tissue specimens were performed at definitive surgery. The clinical data was collected at the whole stage of DDH patients at diagnosis, treatment and follow-up. A total of 528 patients with DDH were enrolled in this study, 90 were men and 438 were women, with the mean age of 4.67 years. The numbers of tissue and blood specimens reached 2172 and 1490, respectively. The quality test results showed that the DNA concentration decreased slightly with the extension of storage time, but the DNA purity did not change. Meanwhile, the extension of storage time slightly affected the stability of protein of tissue samples but did not affect the expression of the housekeeping gene. The DDH biobank built has the potential of monitoring disease pathogenesis and progress, which could provide specimens to the researchers improving the biological understanding and provide guidance of clinical treatment of this disease to clinicians.

Association Analysis of GDF5 and Contributing Factors in Developmental Dysplasia of the Hip in Infants.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a developmental disorder which is reported to be associated with hip instability. When untreated, it can lead to irreversible joint damage. DDH is known to be a multifactorial disease involving genetic, mechanical and environmental factors. The greatest causative potential is attributed to the genetic component. Growth Differentiation Factor 5 (GDF5) is among the most studied genes associated with processes of regeneration and maintenance of joints. The aim of this work was to analyse the association of SNP rs143383 in the GDF5 gene and the occurrence of DDH, along with association with various contributing factors in the Caucasian population. MATERIAL AND METHODS: A total of 118 samples were analysed for the presence of the mutation. DNA was isolated from all individuals from peripheral blood. SNP rs143383 in the GDF5 gene was genotyped using the TaqMan assay. A standard chi-square test was used to compare allele and genotype distributions in patients and healthy controls. RESULTS: The association analysis of genotypes of DDH and rs143383 revealed a significant association. Also, the association of GDF5 and selected contributing factors was statistically significant in female gender (p=0.002), family history (p<0.001), count of pregnancy (p=0.009), laterality of hip involvement and initial US examination. CONCLUSIONS: 1. The results indicate an important effect of rs143383 polymorphism in the GDF5 gene on DDH development. 2. However, our results also suggest that rs143383 is not the only contributing factor in the genetic component of DDH.

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

A structure and function relationship study to identify the impact of the R721G mutation in the human mitochondrial lon protease.

Lon is an ATP-dependent protease belonging to the "ATPase associated with diverse cellular activities" (AAA+) protein family. In humans, Lon is translated as a precursor and imported into the mitochondria matrix through deletion of the first 114 amino acid residues. In mice, embryonic knockout of lon is lethal. In humans, some dysfunctional lon mutations are tolerated but they cause a developmental disorder known as the CODAS syndrome. To gain a better understanding on the enzymology of human mitochondrial Lon, this study compares the structure-function relationship of the WT versus one of the CODAS mutants R721G to identify the mechanistic features in Lon catalysis that are affected. To this end, steady-state kinetics were used to quantify the difference in ATPase and ATP-dependent peptidase activities between WT and R721G. The Km values for the intrinsic as well as protein-stimulated ATPase were increased whereas the kcat value for ATP-dependent peptidase activity was decreased in the R721G mutant. The mutant protease also displayed substrate inhibition kinetics. In vitro studies revealed that R721G did not degrade the endogenous mitochondrial Lon substrate pyruvate dehydrogenase kinase isoform 4 (PDK4) effectively like WT hLon. Furthermore, the pyruvate dehydrogenase complex (PDH) protected PDK4 from hLon degradation. Using hydrogen deuterium exchange/mass spectrometry and negative stain electron microscopy, structural perturbations associated with the R721G mutation were identified. To validate the in vitro findings under a physiologically relevant condition, the intrinsic stability as well as proteolytic activity of WT versus R721G mutant towards PDK 4 were compared in cell lysates prepared from immortalized B lymphocytes expressing the respective protease. The lifetime of PDK4 is longer in the mutant cells, but the lifetime of Lon protein is longer in the WT cells, which corroborate the in vitro structure-functional relationship findings.

25(OH)D status and expression of miR-140 in the serum of patients with developmental dysplasia of the hip.

OBJECTIVES: Developmental dysplasia of the hip (DDH) is one of the most common orthopedic birth defects in newborn infants, for whom early detection and treatment are critical. MiR-140 plays an important role in bone development and was found to be regulated by vitamin D receptors in our previous study. This study aimed to investigate vitamin D status and miR-140 expression in the circulation of patients with orthopedic conditions, including DDH. METHODS: The 25-hydroxyvitamin D (25[OH]D) status and miR-140 expression were determined in the serum of 120 patients with orthopedic conditions. Receiver operating characteristic curves were used to evaluate the potential diagnosis capability of 25(OH)D status and miR-140 expression in DDH. A DDH rat model was also used to verify miR-140 expression in vivo. RESULTS: We found that most patients with orthopedic conditions have vitamin D insufficiency and deficiency, and patients with DDH are in the insufficiency range. MiR-140 was downregulated in the serum of patients with DDH patients and in the hip joints of rats with DDH. A panel of 25(OH)D and miR-140 showed robust performance in distinguishing DDH from controls. CONCLUSIONS: Our results indicate that miR-140 may play an important role in DDH, with the potential capability of being a biomarker for the diagnosis of DDH.

Current knowledge on the genetic background of developmental dysplasia of the hip and the histomorphological status of the cartilage.

Developmental dysplasia of the hip (DDH) represents a morphological abnormality characterized by the incongruity of femoral head and acetabulum. It ranges from mild dysplastic changes to complete dislocation. DDH has been associated with several hereditary and environmental risk factors, which could explain the incidence variability among different countries. Numerous genes may be involved in the disease etiology and progression. However, there are controversies in the literature regarding some of these genes. DDH-induced secondary osteoarthritis (OA) is characterized by changes in the macromolecule content of the cartilage and the expression of cartilage degradation markers. In addition, it exhibits a pattern of specific histological changes, with several reported differences between primary and DDH-induced secondary OA. The articular cartilage of patients with DDH shows specific radiological characteristics, including changes visible already in infancy, but also at pre-arthritic stages, early stages of OA, and in fully developed DDH-induced secondary OA. Although DDH has been extensively researched in different disease stages, the etiology of the disorder still remains uncertain. This review focuses on the current knowledge on the histomorphological status of the cartilage and the genetic background of DDH.

Sacral protuberance with cleft lip and palate: Prenatal presentation of 3MC syndrome.

3MC syndromes are rare heterogeneous autosomal recessive conditions previously designated as Mingarelli, Malpuech, Michels, and Carnevale syndromes, characterized by dysmorphic facial features, facial clefts, growth restriction, and intellectual disability. 3MC is secondary to mutations in the MASP1, MASP3, COLEC11, and COLEC10 genes. The number of patients with 3MC syndrome with known mutations in the COLEC11 or MASP1 is, to date, less than 50. At the time this case presented (2015), the only gene identified in Online Mendelian Inheritance in Man to be associated with 3MC syndrome was MASP1. We present, to the best of our knowledge, the first prenatal report of 3MC syndrome, secondary to a homozygous variant in MASP1. Fetal findings included bilateral cleft lip and palate, abnormality of the sacral spine, a right echogenic pelvic kidney, and brachycephaly. 3MC syndrome should be considered as part of the differential diagnosis when fetal ultrasound detects facial clefts and spinal defects, as the risk of recurrence is significant and a molecularly confirmed diagnosis allows for alternate reproductive options.

Developmental Dysplasia of the Hip: A Review of Etiopathogenesis, Risk Factors, and Genetic Aspects.

As one of the most frequent skeletal anomalies, developmental dysplasia of the hip (DDH) is characterized by a considerable range of pathology, from minor laxity of ligaments in the hip joint to complete luxation. Multifactorial etiology, of which the candidate genes have been studied the most, poses a challenge in understanding this disorder. Candidate gene association studies (CGASs) along with genome-wide association studies (GWASs) and genome-wide linkage analyses (GWLAs) have found numerous genes and loci with susceptible DDH association. Studies put major importance on candidate genes associated with the formation of connective tissue (COL1A1), osteogenesis (PAPPA2, GDF5), chondrogenesis (UQCC1, ASPN) and cell growth, proliferation and differentiation (TGFB1). Recent studies show that epigenetic factors, such as DNA methylation affect gene expression and therefore could play an important role in DDH pathogenesis. This paper reviews all existing risk factors affecting DDH incidence, along with candidate genes associated with genetic or epigenetic etiology of DDH in various studies.

Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.

Arthrochalasia Ehlers-Danlos syndrome (aEDS) is a rare autosomal dominant connective tissue disorder that is characterized by congenital bilateral hip dislocations, severe generalized joint hypermobility, recurrent joint (sub)luxations, and skin hyperextensibility. To date, 42 patients with aEDS have been published. We report 12 patients with aEDS from 10 families with 6 unpublished individuals and follow-up data on 6 adult patients. The clinical features are largely comparable with patients reported in the literature. Most (n = 10) patients had variants leading to (partial) loss of exon 6 of the COL1A1 or COL1A2 genes. One patient did not have a previously reported likely pathogenic COL1A1 variant. Data regarding management were retrieved. Hip surgery was performed in 5/12 patients and 3/12 patients underwent spinal surgery. As much as 4/12 patients were wheelchair-bound or unable to walk unaided. Fractures were present in 9/12 individuals with 1 patient requiring bisphosphonate treatment. Echocardiograms were performed in 10 patients and 2 individuals showed an abnormality likely unrelated to aEDS. One patient gave birth to two affected children and went through preterm labor requiring medication but had no additional complications. Of the eight adults in our cohort, the majority entered a career. Our data point toward a genotype-phenotype relationship with individuals with aEDS due to pathogenic COL1A1 variants causing complete or partial loss of exon 6 being more severely affected regarding musculoskeletal features. There is a significant lack of knowledge with regard to management of aEDS, particularly in adulthood. As such, systematic follow-up and multidisciplinary treatment is essential.

Genetic Predisposition to Developmental Dysplasia of the Hip.

BACKGROUND: The etiopathogenesis of developmental dysplasia of the hip (DDH) has not been clarified. This systematic review evaluated current literature concerning all known chromosomes, loci, genes, and their polymorphisms that have been associated or not with the prevalence and severity of DDH. METHODS: Following the established methodology of Meta-analysis of Observational Studies in Epidemiology guidelines, MEDLINE, EMBASE, and Cochrane Register of Controlled Trials were systematically searched from inception to January 2019. RESULTS: Forty-five studies were finally included. The majority of genetic studies were candidate gene association studies assessing Chinese populations with moderate methodological quality. Among the most frequently studied are the first, third, 12th,17th, and 20th chromosomes. No gene was firmly associated with DDH phenotype. Studies from different populations often report conflicting results on the same single-nucleotide polymorphism (SNP). The SNP rs143384 of GDF5 gene on chromosome 20 demonstrated the most robust relationship with DDH phenotype in association studies. The highest odds of coinheritance in linkage studies have been reported for regions of chromosome 3 and 13. Five SNPs have been associated with the severity of DDH. Animal model studies validating previous human findings provided suggestive evidence of an inducing role of mutations of the GDF5, CX3CR1, and TENM3 genes in DDH etiopathogenesis. CONCLUSION: DDH is a complex disorder with environmental and genetic causes. However, no firm correlation between genotype and DDH phenotype currently exists. Systematic genome evaluation in studies with larger sample size, better methodological quality, and assessment of DDH patients is necessary to clarify the DDH heredity. The role of next-generation sequencing techniques is promising.

Namaqualand hip dysplasia in South Africa: The molecular determinant elucidated.

BACKGROUND: Namaqualand hip dysplasia (NHD) is a mild form of spondyloepiphyseal dysplasia in which progressive arthropathy of the hip joint is a major manifestation. The disorder was documented in a multigenerational South African (SA) family with antecedents from Namaqualand, a region in the north-west of the country. Linkage analysis revealed a locus that includes the collagen type II gene, COL2A1. OBJECTIVES: To identify the pathogenic COL2A1 variant causing NHD in an SA family. METHODS: One affected male with a clear diagnosis of NHD was selected for whole-exome sequencing (WES) on the Ion Torrent Proton platform. A probe-based assay and direct cycle sequencing were used to confirm that the prioritised variant segregated with the phenotype in the NHD family and was not present in unrelated controls from the same population. RESULTS: WES identified one heterozygous variant, c.2014G>T; p.(Gly672Cys), in the coding sequence of the COL2A1 gene. The variant segregated with NHD in 23 affected family members and was previously reported in a Caucasian male with Perthes disease-like presentation. CONCLUSIONS: It is now possible to provide a molecular diagnosis of NHD before hip problems present. The large, clinically well-characterised NHD family is a valuable resource that could provide more insight into the mechanisms responsible for the variable expression observed in individuals with this variant.

Demography, heritability and genetic correlation of feline hip dysplasia and response to selection in a health screening programme.

Feline hip dysplasia (FHD) is a debilitating condition affecting the hip joints of millions of domestic cats worldwide. Despite this, little is known about FHD except that it is relatively common in the large breed Maine Coon. We used 20 years of data from 5038 pedigree-registered Maine Coon cats in a radiographic health screening programme for FHD to determine, for the first time, its heritability, genetic correlation to body mass and response to selection. FHD prevalence was 37.4%, with no sex predilection; however, FHD severity increased with age and body mass. Heritability of the radiographic categories used to classify FHD severity was 0.36 (95%CI: 0.30-0.43). The severity of FHD symptoms was also genetically correlated with body mass (0.285), suggesting that selection for a large body type in this breed concurrently selects for FHD. Support for this was found by following generational responses to selective breeding against FHD. Not only did selective breeding successfully reduce the severity of FHD symptoms in descendants, but these cats were also smaller than their ancestors (-33g per generation). This study highlights the value of breeding programmes against FHD and cautions against breed standards that actively encourage large bodied cats.

Abnormal expression of Pappa2 gene may indirectly affect mouse hip development through the IGF signaling pathway.

INTRODUCTION: Developmental dysplasia of the hip (DDH) is a major cause of disability in children, and the genetic mechanism of this disease remains unclear. In our previous study, we found that pregnancy-associated plasma protein-A2 (PAPP-A2) was associated with DDH significantly. OBJECTIVES: The aim of this study was to investigate the insulin-like growth factor (IGF) expression and collagen synthesis as well as cartilage proliferation-related proteins in the case of abnormal expression of Pappa2 in mice to research the relationship between PAPP-A2 and the pathological changes of DDH. METHODS: In vivo animal experiments, the mice were directly injected with 50 µl of Cas9/PAPP-A2 sgRNA lentiviruses around the hip to downregulate the Pappa2 gene expression and injected with control lentiviruses on the other side, then to observe the expression and localization of related proteins. And in an in vitro experiment, mice fibroblasts and primary chondrocytes were cultured with insulin-like growth factor binding protein-5 (IGFBP-5) protein, PAPP-A2 protein and Cas9/PAPP-A2 sgRNA lentiviruses to detect of related proteins and mRNA expression. RESULTS: Cartilage proliferation-related proteins demonstrated a significant decrease in the PAPP-A2 knockdown hips acetabulum and femoral head cartilage, meanwhile the IGF expression was also downregulated in the soft tissue around the acetabulum compared with the control hips. Furthermore, the role PAPP-A2 played in chondrocytes and fibroblasts was the same as in the in vivo experiments, downregulation of PAPP-A2 expression or upregulation of IGFBP-5 expression can reduce collagen synthesis and cartilage proliferation. CONCLUSIONS: PAPP-A2 may be involved in the development of the mouse hip joint by interfering the fibrous and cartilaginous metabolism via IGF pathway-associated proteins pathway.

The H19/let-7 feedback loop contributes to developmental dysplasia and dislocation of the hip.

Developmental dysplasia and dislocation of the hip (DDH) is the most common type of lower limb deformity in pediatric orthopedics. The mechanism of the signaling pathway has been studied in depth. However, the role of epigenetic regulation, such as lncRNA, is still far from clear. In this study, we successfully established a rat model of DDH and demonstrated that H19 was down-regulated in the development of DDH. Further, we constructed H19 knockdown (KD) and overexpression chondrocytes. H19 KD suppressed the proliferation of normal chondrocytes, while overexpression of H19 promoted cell proliferation of DDH chondrocytes. Finally, we revealed that H19 bound to let-7 and inhibited its function, acting as a competing endogenous RNA. Down-regulation of H19 is closely associated with DDH progression and H19 is an important epigenetic factor that regulates the proliferation of chondrocytes. H19 may thus be a potential clinical marker for DDH diagnosis and treatment.