If the stem cells in cartilage tissue remain spry, they can help slow the development of osteoarthritis, or “wear and tear” arthritis, the most common chronic condition of the joints. Unfortunately, these stem cells all too frequently succumb to nucleolar instability, fall into senescence, and contribute to physiological and pathological aging. To prevent nucleolar instability—and ensure that stem cells remain capable of differentiating into mature cells such as osteoblasts, chondrocytes, and adipocytes—scientists at the Chinese Academy of Sciences have proposed a form of gene therapy.

The gene therapy is designed to enhance the protective effect of CBX4, a component of polycomb repressive complex 1 (PRC1) that plays an important role in the regulation of cell identity and organ development through gene silencing. According to the Chinese Academy team, the stabilizing influence of CBX4 definitely extends to human stem cells. Moreover, the team demonstrated that inducing the overexpression of CBX4 alleviates stem cell aging and attenuates the development of osteoarthritis, highlighting a potential avenue for the use of CBX4 gene therapy vector in treating aging and aging-related disorders.

Details of this work appeared March 27 in the journal Cell Reports, in an article titled, “Maintenance of Nucleolar Homeostasis by CBX4 Alleviates Senescence and Osteoarthritis.” The article describes how lentiviruses encoding CBX4 or Luc (control) were administered into the joint capsules of experimental mice. It also relates how microcomputed tomography revealed that CBX4-based gene therapy increased the bone density of the joint at 8 weeks after surgically induced osteoarthritis.

“CBX4 protein is downregulated in aged human mesenchymal stem cells (MSCs), whereas CBX4 knockout in hMSCs results in destabilized nucleolar heterochromatin, enhanced ribosome biogenesis, increased protein translation, and accelerated cellular senescence,” the article’s authors wrote. “CBX4 maintains nucleolar homeostasis by recruiting nucleolar protein fibrillarin (FBL) and heterochromatin protein KRAB-associated protein 1 (KAP1) at nucleolar rDNA, limiting the excessive expression of rRNAs.”

Graphical abstract from the Cell Reports article indicating that CBX4 maintains nucleolar homeostasis and alleviates senescence and osteoarthritis. [IOZ]

Importantly, overexpression of CBX4 alleviated physiological hMSC aging and attenuated the development of osteoarthritis in mice.

These findings not only highlight that CBX4-mediated nucleolar homeostasis is a key gatekeeper for hMSC aging. They also open an avenue for preventing aging-associated stem cell exhaustion and, hopefully, treating age-related disorders in the future.

Taken together, the researchers revealed a new mechanism for the nucleolar protein CBX4 in maintaining hMSC homeostasis.

These findings suggest the feasibility of using gene therapy strategies to rejuvenate senescent cells and treat osteoarthritis, providing a promising option for future geriatrics and regenerative medicine.

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