Males and Females Have Distinct Molecular Events in the Articular Cartilage during Knee Osteoarthritis

Abstract

Osteoarthritis (OA) is a major public health challenge that imposes a remarkable burden on the affected individuals and the healthcare system. Based on the clinical observation, males and females have different prevalence rates and severity levels of OA. Thus, sex-based differences may play essential roles in OA’s prognosis and treatment outcomes. To date, the comprehensive understanding of the relationship between sex and OA is still largely lacking. In the current study, we analyzed a published transcriptome dataset of knee articular cartilage (GSE114007) from 18 healthy (five females, 13 males) and 20 OA (11 females, nine males) donors to provide a slight insight into this important but complex issue. First, comparing female healthy cartilage samples with those of males revealed 36 differential expression genes (DEGs), indicating the fundamental sex-related differences at the molecular level. Meanwhile, 923 DEGs were distinguished between OA and healthy female cartilage, which can be enriched to 15 Reactome pathways. On the other hand, when comparing OA and healthy male cartilage, there are only 419 DEGs were identified, and only six pathways were enriched against the Reactome database. The different signaling response to OA in the male and female cartilage was further enforced by recognizing 50 genes with significantly different OA-responsive expression fold changes in males and females. Particularly, 14 Reactome pathways, such as “Extracellular matrix organization”, “Collagen biosynthesis and modifying enzymes”, “Dissolution of fibrin clot”, and “Platelet Aggregation (Plug formation)”, can be noted from these 50 sex-dependent OA-responsive genes. Overall, the current study explores the Sex as a Biological Variable (SABV) at the transcriptomic level in the knee articular cartilage in both healthy status and OA event, which could help predict the differential OA prognosis and treatment outcome of males and female patients.

Identification of SCRG1 as a Potential Therapeutic Target for Human Synovial Inflammation

“…For the six marker genes previously identified, we found that CDKN1A, FOSB, STMN2, and SLC2A3 genes were reported to be associated with cartilage inflammation in OA (40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51). For example, the expression level of CDKN1A will increase correspondingly during cartilage degeneration (44), IL-17 and IL-1beta induced collagenase-3 production through AP-1 occurred with differential protein complex, and stimulation resulted in FOSB activation (52), STMN2 has significant differences between preserved and subchondral bone (48).…”

Gender-Related Aspects in Osteoarthritis Development and Progression: A Review

“…The hyaline cartilage of the involved joint is still considered the major target for clinical and molecular research in humans. A recent study conducted by Li et al [ 15 ] demonstrated that cartilage has different gene expression between males and females, even in healthy joints: for example, TSIX transcript and XIST antisense RNA ( TSIX ) expression are significantly higher in females, although their function in the articular microenvironment is still under investigation. Moreover, most of the genes linked to OA onset are more involved in extracellular matrix turnover in females than in males.…”

“…For instance, FOXO -mediated transcription factors are elevated in females’ osteoarthritic joints [ 34 , 64 , 65 ]. Conversely, in males, the PERK-ATF4-CHOP axis seems to be more involved in cartilage degeneration [ 15 , 66 ]. Male cartilage has also a lower expression of IGFAL , which encodes for a protein binding IGFs and increasing its half-life: therefore, the IGF-1 pathway seems to be less activated in males than in females [ 67 , 68 ].…”

“…At the gene expression level, OA onset and progression is sustained by different upregulation and downregulation of genes in males and females; even if the exact mechanisms involved are still unknown, the impaired extracellular matrix turnover seems to be more involved in cartilage degeneration in female patients [ 15 ].…”

“…Furthermore, OA development can be triggered by the steep decline of sex hormone levels in the menopause [ 13 , 14 ]. Sex-related differences in the onset and progression of OA have been the subject of a number of studies, and there is increasing interest in this topic, with new data constantly brought to the attention of scientists [ 14 , 15 ]. Therefore, the present review aims to provide an updated summary of the most recent evidence on the gender-related mechanisms of OA, including the hormone-determined, anatomical, molecular, and biomechanical aspects, as well as their interconnections.…”