Distinctiveness of Femoral and Acetabular Mesenchymal Stem and Progenitor Populations in Patients with Primary and Secondary Hip Osteoarthritis Due to Developmental Dysplasia.

Primary hip osteoarthritis (pOA) develops without an apparent underlying reason, whereas secondary osteoarthritis arises due to a known cause, such as developmental dysplasia of the hips (DDH-OA). DDH-OA patients undergo total hip arthroplasty at a much younger age than pOA patients (50.58 vs. 65 years in this study). Recently, mesenchymal stem and progenitor cells (MSPCs) have been investigated for the treatment of osteoarthritis due to their immunomodulatory and regenerative potential. This study identified cells in subchondral bone expressing common MSPC markers (CD10, CD73, CD140b, CD146, CD164, CD271, GD2, PDPN) in vivo and compared the proportions of these populations in pOA vs. DDH-OA, further correlating them with clinical, demographic, and morphological characteristics. The differences in subchondral morphology and proportions of non-hematopoietic cells expressing MSPC markers were noted depending on OA type and skeletal location. Bone sclerosis was more prominent in the pOA acetabulum (Ac) in comparison to the DDH-OA Ac and in the pOA Ac compared to the pOA femoral head (Fh). Immunophenotyping indicated diagnosis-specific differences, such as a higher proportion of CD164+ cells and their subsets in DDH-OA, while pOA contained a significantly higher proportion of CD10+ and GD2+ cells and subsets, with CD271+ being marginally higher. Location-specific differences showed that CD271+ cells were more abundant in the Fh compared to the Ac in DDH-OA patients. Furthermore, immunohistochemical characterization of stromal bone-adjacent cells expressing MSPC markers (CD10, CD164, CD271, GD2) in the Ac and Fh compartments was performed. This research proved that immunophenotype profiles and morphological changes are both location- and disease-specific. Furthermore, it provided potentially effective targets for therapeutic strategies. Future research should analyze the differentiation potential of subsets identified in this study. After proper characterization, they can be selectively targeted, thus enhancing personalized medicine approaches in joint disease management.

MicroRNA-34a-5p promotes the progression of osteoarthritis secondary to developmental dysplasia of the hip by restraining SESN2-induced autophagy.

Osteoarthritis (OA), a late-stage complication of developmental dysplasia of the hip (DDH), is a key factor leading to further degeneration of joint function. Studies have shown that Sestrin2 (SESN2) is a positive regulator in protecting articular cartilage from degradation. However, the regulatory effects of SESN2 on DDH-OA and its upstream regulators remain obscure. Here, we first identified that the expression of SESN2 significantly decreased in the cartilage of DDH-OA samples, with an expression trend negatively correlated with OA severity. Using RNA sequencing, we identified that the upregulation of miR-34a-5p may be an important factor for the decrease in SESN2 expression. Further exploring the regulation mechanism of miR-34a-5p/SESN2 is of great significance for understanding the mechanism of DDH occurrence and development. Mechanistically, we showed that miR-34a-5p could significantly inhibit the expression of SESN2, thereby promoting the activity of the mTOR signaling pathway. We also found that miR-34a-5p significantly inhibited SESN2-induced autophagy, thereby suppressing the proliferation and migration of chondrocytes. We further validated that knocking down miR-34a-5p in vivo resulted in a significant increase in SESN2 expression and autophagy activity in DDH-OA cartilage. Our study suggests that miR-34a-5p is a negative regulator of DDH-OA, and may provide a new target for the prevention of DDH-OA.

Are vitamin D and vitamin D receptor levels different in children with developmental dysplasia of the hip?

INTRODUCTION: Developmental dysplasia of the hip (DDH) is a common disorder and associated with significant morbidity of the hip joint. Several risk factors have been identified for DDH. The aim of this study is to investigate whether vitamin D and vitamin D receptor (VDR) levels differ in children with DDH and whether they have an effect on DDH development. MATERIALS AND METHODS: A total of 40 (17 males, 23 females; 9 right hips, 16 left hips, 15 bilateral hips) children who were treated for developmental dysplasia and 40 (23 males, 17 females) healthy children without any musculoskeletal system and metabolic disorders were included in this study between January and June 2019. Blood samples from the DDH and control groups of children were collected to measure the serum levels of vitamin D, VDR, calcium (Ca), phosphorus (P), and alkaline phosphatase (ALP). The levels of Ca, P, and ALP were analyzed using the automated standard spectrophotometric laboratory method. The levels of vitamin D and VDR in the samples were analyzed using enzyme-linked immunoassay. RESULTS: There were no significant differences in the serum levels of Ca, P, ALP, and vitamin D between the DDH and healthy groups (Ca 9.96 ± 0.47 vs. 9.92 ± 0.48 mg/dL, respectively, p = 0.721; P 5.3 ± 0.94 vs. 4.82 ± 0.88 mg/dL, respectively, p = 0.23; ALP 252.22 ± 170.15 vs. 245.3 ± 130.93 U/L, respectively, p = 0.839). However, serum VDR levels were significantly lower in children in the DDH group (5.77 ± 3.51 ng/mL) than in the healthy control group (9.25 ± 6.43 ng/mL) (p = 0.004). CONCLUSIONS: In conclusion, we believe that low VDR levels can affect DDH regardless of the serum levels of Ca, P, ALP, and vitamin D. More comprehensive studies involving parents are needed to understand whether VDR levels mediate genetic transmission in DDH or not.

Genetic variant of COL11A2 gene is functionally associated with developmental dysplasia of the hip in Chinese Han population.

OBJECTIVES: Developmental dysplasia of the hip (DDH) is a common skeletal disorder. This study was conducted to demonstrate the association between DDH and a polymorphism rs9277935 of COL11A2 gene. RESULTS: A significant difference in genotype distribution in a recessive model (TT+GT vs. GG) between two groups (P=0.017) was demonstrated. Analysis in female patients showed significantly greater frequency of minor allele G(0.49 vs. 0.43, p=0.024) and significantly higher distribution of GG genotype (p=0.006). DDH patients were found to have significantly lower COL11A2 expression than controls. Moreover, DDH patients with rs9277935 genotype TT have a significantly increased expression of COL11A2 than those with genotype GG. COL11A2 demonstrated chondrogenic properties in vitro. CONCLUSION: Polymorphism rs9277935 of gene COL11A2 is a functional variant regulating the expression and the chondrogenic properties of COL11A2 in DDH in Chinese Han population. METHODS: A case-control candidate gene association study was conducted in 945 patients (350 radiologically confirmed DDH patients and 595 healthy controls). Difference of COL11A2 expression in hip joint tissue was compared between the patients and the controls. Allelic difference in Col11a2 expression by rs9277935 was assessed with luciferase activity. Chondrogenic effects of Col11a2 signaling on BMSCs were also determined in vitro.

Chondrocyte suppression is mediated by miR-129-5p via GDF11/SMAD3 signaling in developmental dysplasia of the hip.

Recent studies have shown that developmental dysplasia of the hip (DDH) during childhood and in animal models is associated with impaired endochondral ossification of the roof of the acetabulum, yet the molecular mechanism of this pathology remains unknown. To address this, an animal model of DDH was established in 4-week-old New Zealand white rabbits by cast immobilization of knee extension. Fifty-six rabbits of DDH were involved in this study, including 21 male rabbits and 25 female rabbits. High-throughput RNA sequencing identified 18 differentially expressed microRNAs; miR-129-5p downregulation was further confirmed by quantitative polymerase chain reaction. Bioinformatics and luciferase reporter assay identified growth differentiation factor 11 (GDF11) as the target gene of miR-129-5p in vitro. miR-129-5p downregulation increased GDF11 expression, which induced the phosphorylation of SMAD family member 3. As a result, the expression of runt-related transcription factor 2, Indian hedgehog homolog, and collagen type X was inhibited in vitro. Meanwhile, Alizarin Red S and Von Kossa staining revealed reduced formation of mineralized nodules by chondrocytes after miR-129-5P downregulation compared with the control. Additionally, proliferation assays and flow cytometry confirmed the suppression of chondrocyte proliferation and G1 cell cycle arrest following miR-129-5p downregulation. These findings indicate that miR-129-5p is able to suppress chondrocyte proliferation and hypertrophic differentiation and decrease mineralization via the miR-129-5p/GDF11/SMAD3 axis. This could present the underlying cause for the observed DDH-associated ossification impairment of the acetabular roof.