MYDGF, a telomerase-activating factor, emerges as a new target for restoring cartilage homeostasis
Background
Osteoarthritis is a disease in which articular cartilage is gradually lost due to impaired chondrocyte function and disrupted balance between synthesis and degradation of the extracellular matrix. In aged chondrocytes, telomere shortening, oxidative stress, and cellular senescence are commonly observed, but the upstream regulators linking telomerase activity and cartilage homeostasis remain insufficiently understood. Current treatments are primarily focused on reducing pain and inflammation, with limited ability to alter the biological state of damaged cartilage.
The research team focused on myeloid-derived growth factor (MYDGF). MYDGF is a secreted protein involved in heart injury recovery and inflammatory responses, but its role in chondrocytes and telomerase remains unclear. The central question of the study was whether MYDGF regulates the telomerase reverse transcriptase (TERT) and whether this regulation translates into cartilage protection in vivo.
Key Findings
The research team performed a whole-genome CRISPR-Cas9 screen in HeLa cells with a TERT promoter fused to green fluorescent protein (GFP). Using MAGeCK analysis, MYDGF was identified as a significant positive regulator (p<0.01). MYDGF inhibition reduced TERT transcription and telomerase activity, while overexpression increased both. These results were reproducible in HeLa cells, the chondrocyte lineage ATDC5, and E14 embryonic stem cells, with key experiments repeated in triplicate.
Exposure to purified recombinant MYDGF protein also increased telomerase activity in a dose-dependent manner across multiple cell lines. The effect was completely blocked by the clathrin-mediated endocytosis inhibitor Dyngo-4a. Activity was also reduced when intracellular calcium was removed using BAPTA-AM or extracellular calcium was depleted, indicating that MYDGF requires calcium-dependent signaling pathways after internalization. MYDGF overexpression also increased Akt phosphorylation at Ser473, and this effect was blocked by the Akt inhibitor MK2206.
In vivo effects were evaluated in mice with surgically induced osteoarthritis via destabilization of the medial meniscus (DMM). Among 22 mice analyzed, MYDGF knockout mice showed more severe cartilage erosion and proteoglycan loss at 8 weeks post-surgery, with higher histological scores according to the Osteoarthritis Research Society International (OARSI). Conversely, intra-articular injection of AAV-MYDGF into the knee joint preserved cartilage surface and proteoglycan better than the control AAV-GFP group. Subchondral bone sclerosis was also reduced, although the sample size in the treatment group was limited to three mice per group. Advanced Biotechnology paper
Implications and Outlook
Transcriptome analysis revealed that MYDGF-deficient chondrocytes showed reduced expression of matrix-related genes such as Col2a1 and Aggrecan, as well as suppressed PI3K-Akt signaling, while immune and inflammatory pathways were activated. The research team interpreted these findings to suggest that MYDGF supports telomerase and Akt survival signaling to maintain chondrocyte synthetic capacity and stress resistance. This study thus proposes a candidate that regulates chondrocyte state at a higher level, beyond merely inhibiting matrix degradation.
However, whether MYDGF actually extends telomeres in vivo remains unmeasured, and the causal relationship between increased telomerase activity and cartilage protection has yet to be proven. The receptor for MYDGF, the sequence of calcium signaling and PI3K-Akt pathways, and the potential risks of long-term telomerase stimulation, such as abnormal cell proliferation or tumor formation, remain unresolved. Efficacy, dosage, and duration must be validated in human primary chondrocytes and large animal osteoarthritis models to assess clinical potential.
Osteoarthritis (OA) involves progressive cartilage breakdown. This is driven by impaired chondrocyte function and an imbalance in the extracellular matrix homeostasis. However, the key upstream regulators that maintain healthy chondrocytes are still not fully known. Here, we report that myeloid-derived growth factor (MYDGF) is a novel regulator of telomerase activity and is critical for cartilage health. Using a genome-wide CRISPR-Cas9 screen with a TERT reporter system, MYDGF was identified as a strong positive regulator of telomerase. Functional studies confirmed that MYDGF positively regulates TERT expression and telomerase activity in both HeLa and ATDC5 cells. In a mouse surgical destabilization of the medial meniscus (DMM) OA model, MYDGF knockout (KO) mice exhibited more severe cartilage damage. Conversely, delivering MYDGF into the knee joint using AAV virus partially alleviated cartilage injury. Transcriptome profiling revealed that MYDGF-deficient chondrocytes exhibit downregulated key pathways involved in matrix building and upregulated inflammatory signals, indicating a shift in cell state. In summary, our work establishes MYDGF as a key upstream factor for both telomerase and cartilage matrix homeostasis remodeling. It connects telomerase function to chondrocyte health. These findings also highlight MYDGF as a promising new target for treating osteoarthritis.
In clinical development, MYDGF protein or gene delivery vectors could be locally administered into the joint space to delay functional decline in chondrocytes of patients with early- to mid-stage osteoarthritis. This approach could be combined with existing analgesics or anti-inflammatory drugs to reduce systemic exposure. For the biotechnology industry, multiple development pathways are open, including MYDGF receptor modulators, endocytosis-enhancing formulations, and low-molecular-weight drugs that mimic downstream signaling.
Before practical application, reproducibility in human cartilage, immune responses to repeated administration, long-term expression control of AAV, and tumor safety must be confirmed. Whether synovial fluid MYDGF or TERT activity levels serve as predictive biomarkers for treatment response should also be validated in prospective patient studies.