Biology subjects

Delco, M. L.

Publications and source records attributed to Delco, M. L..

3 recordsLinked to original sources

bioRxiv2026

Loss of connexin 43 in cartilage causes mitochondrial dysfunction and accelerates post-traumatic osteoarthritis progression

Osteoarthritis (OA) is a major cause of chronic pain and disability worldwide, characterized by progressive degeneration of cartilage and subchondral bone. Post-traumatic OA (PTOA) develops in as many as 25-50% of individuals following major joint injury, making it a leading cause of OA in younger and otherwise healthy populations.1,2 Connexin 43 (Cx43), a gap junction protein involved in intercellular communication and cellular stress responses, has been linked to OA; however, its role in the progression of PTOA remains unclear. Here, we examined how cartilage-specific loss of Cx43 influences PTOA and chondrocyte metabolic function. Using a murine model of conditional Cx43 deletion in cartilage, we demonstrate that male knockout mice exhibited severe cartilage surface damage and matrix loss, whereas female knockout mice showed cartilage thinning accompanied by reduced chondrocyte hypertrophy, decreased subchondral bone density, and increased osteophyte formation. Thus, loss of Cx43 disrupts cartilage integrity and osteochondral remodeling in a sex-specific manner, predisposing joints to maladaptive bone changes and cartilage degeneration. Complementary mechanistic studies in human articular chondrocytes revealed that Cx43 deficiency impairs mitochondrial respiration, reduces spare respiratory capacity, and lowers ATP production, consistent with compromised cellular bioenergetics. Together, these findings identify Cx43 as an important coordinator of metabolic and structural responses to joint injury. These results position Cx43 as a context-dependent regulator of joint homeostasis and suggest that maintenance of Cx43 expression may support cartilage resilience following injury.

cell biology↗

bioRxiv2024

Connexin 43 Regulates Intercellular Mitochondrial Transfer from Human Mesenchymal Stromal Cells to Chondrocytes

BackgroundThe phenomenon of intercellular mitochondrial transfer from mesenchymal stromal cells (MSCs) has shown promise for improving tissue healing after injury and has potential for treating degenerative diseases like osteoarthritis (OA). Recently MSC to chondrocyte mitochondrial transfer has been documented, but the mechanism of transfer is unknown. Full-length connexin43 (Cx43, encoded by GJA1) and the truncated internally translated isoform GJA1-20k have been implicated in mitochondrial transfer between highly oxidative cells, but have not been explored in orthopaedic tissues. Here, our goal was to investigate the role of Cx43 in MSC to chondrocyte mitochondrial transfer. In this study, we tested the hypotheses that (a) mitochondrial transfer from MSCs to chondrocytes is increased when chondrocytes are under oxidative stress and (b) MSC Cx43 expression mediates mitochondrial transfer to chondrocytes. MethodsOxidative stress was induced in immortalized human chondrocytes using tert-Butyl hydroperoxide (t-BHP) and cells were evaluated for mitochondrial membrane depolarization and reactive oxygen species (ROS) production. Human bone-marrow derived MSCs were transduced for mitochondrial fluorescence using lentiviral vectors. MSC Cx43 expression was knocked down using siRNA or overexpressed (GJA1+ and GJA1-20k+) using lentiviral transduction. Chondrocytes and MSCs were co-cultured for 24 hrs in direct contact or separated using transwells. Mitochondrial transfer was quantified using flow cytometry. Co-cultures were fixed and stained for actin and Cx43 to visualize cell-cell interactions during transfer. ResultsMitochondrial transfer was significantly higher in t-BHP-stressed chondrocytes. Contact co-cultures had significantly higher mitochondrial transfer compared to transwell co-cultures. Confocal images showed direct cell contacts between MSCs and chondrocytes where Cx43 staining was enriched at the terminal ends of actin cellular extensions containing mitochondria in MSCs. MSC Cx43 expression was associated with the magnitude of mitochondrial transfer to chondrocytes; knocking down Cx43 significantly decreased transfer while Cx43 overexpression significantly increased transfer. Interestingly, GJA1-20k expression was highly correlated with incidence of mitochondrial transfer from MSCs to chondrocytes. ConclusionsOverexpression of GJA1-20k in MSCs increases mitochondrial transfer to chondrocytes, highlighting GJA1-20k as a potential target for promoting mitochondrial transfer from MSCs as a regenerative therapy for cartilage tissue repair in OA.

bioengineering↗

bioRxiv2021

Synovial Fluid Mitochondrial DNA Concentration Reflects the Degree of Cartilage Damage After Naturally Occurring Articular Injury

Posttraumatic osteoarthritis (PTOA) is a debilitating sequela to joint injury with no current therapeutics that can slow its progression. Early intervention, prior to the development of degenerative joint changes, has the potential for greater therapeutic success but requires early detection of joint injury. In other tissue types, trauma is associated with the extracellular release of mitochondrial DNA (mtDNA), which serves as a mitochondria-specific Damage Associated Molecular Pattern (mDAMP) to perpetuate inflammation. We demonstrated that chondrocytes release mtDNA following cellular stress and that mtDNA is increased in equine synovial fluid following experimental and naturally occurring mechanical injury to the joint surface. Moreover, we found a strong correlation between the degree of cartilage damage and mtDNA concentration. Finally, impact-induced mtDNA release was mitigated by mitoprotective treatment. These data suggest synovial fluid mtDNA may represent a sensitive marker of early articular injury, prior to the onset of changes on standard diagnostic imaging modalities. One Sentence SummarySynovial fluid mitochondrial DNA increases after articular injury, is associated with the degree of cartilage damage, and is mitigated by mitoprotective treatment.

cell biology↗