Identification of CaMK4 as a sex-difference-related gene in knee osteoarthritis

Abstract

Background: Osteoarthritis (OA) is a common degenerative joint disease with a higher prevalence in females than in males. Sex may be a key factor affecting the progression of OA. This study aimed to investigate critical sex-difference-related genes in patients with OA and confirm their potential roles in OA regulation.Methods: OA datasets GSE12021, GSE55457, and GSE36700 were downloaded from the Gene Expression Omnibus database to screen OA-causing genes that are differentially expressed in the two sexes.Cytoscape was used to construct a protein-protein interaction network and determine hub genes. Synovial tissues of patients (male and female) with OA and female non-OA healthy controls were obtained to confirm the expression of hub genes and screen the key genes among them. Destabilization of the medial meniscus (DMM)-induced OA mice model was established to verify the screened key genes. Hematoxylin and eosin (HE) staining and Safranin O-fast green dye staining were employed to observe synovial inflammation and pathological cartilage status.Results: The abovementioned three datasets were intersected to obtain 99 overlapping differentially expressed genes, of which 77 were upregulated and 22 were downregulated in female patients with OA.The hub genes screened were EGF, AQP4, CDC42, NTRK3, ERBB2, STAT1, and CaMK4. Among them, Ca 2+ /calmodulin-dependent protein kinase-4 (CaMK4) was identified as a key sex-related gene for OA. It was significantly higher in female OA patients than in the cases of male patients. Moreover, CaMK4 was significantly increased in female patients with OA compared with the female non-OA group. These results suggest that CaMK4 plays an important role in the progression of OA. OA mouse models demonstrated that CaMK4 expression in the mice knee joint synovial tissue elevated after DMM, with aggravated synovial inflammation and significant cartilage damage. Cartilage damage improved after intraperitoneal administration of the CaMK4 inhibitor KN-93.Conclusions: CaMK4 is a key sex-related gene influencing the progression and pathogenesis of OA and may be considered as a new target for OA treatment.

Closing the gap: sex-related differences in osteoarthritis and the ongoing need for translational studies

“…To further investigate the role of CaMK4, OA was induced in mice by medial meniscal destabilization and the efficacy of early KN-93, a potent CaMK4 inhibitor, was evaluated. KN-93 administration was chondroprotective, further supporting the role of CaMK4 in OA ( 14 ). CaMK4 is an important member of the calmodulin-dependent kinase family known to be mainly distributed in the brain, thymus and bone marrow and not yet linked to musculoskeletal diseases.…”

“…A recent study by Feng et al screened some of the same datasets as previous studies for hub genes ( 14 ). The study confirmed previously identified genes including EGF, EGFR, CDC42, AQP4, and STAT 1 in addition to NTRK3 and CaMK4; neither NTRK3 nor CaMK4 have been previously linked to OA pathogenesis.…”

“…CaMK4 is an important member of the calmodulin-dependent kinase family known to be mainly distributed in the brain, thymus and bone marrow and not yet linked to musculoskeletal diseases. CaMK4 plays an intricate role in orchestrating the immune response, is a known inhibitor of IL-2 (a cytokine essential to the differentiation of regulatory T-helper cells), and promotes inflammatory cytokine and chemokine expression ( 14 ). Interestingly, IL-2 acts via downstream signalling pathways including the PI3K-Akt pathway thereby providing a potential mechanism of OA pathogenesis ( 15 ).…”

Nuclear Binding Protein 2/Nesfatin-1 Affects Trophoblast Cell Fusion during Placental Development via the EGFR-PLCG1-CAMK4 Pathway

“…A study demonstrated that calmodulin-dependent protein kinase IV (CAMK4) is closely related to trophoblast function. It was also found that EGFR affects the activation of phospholipase C gamma 1 (PLCG1) and CAMK4 [24]. However, the role and mechanism of NUCB2/Nesfatin-1 in human placental syncytial disorder requires further study.…”