z-bio 2025-07-30 4395

　　Osteoarthritis (OA) is a common degenerative joint disease that mainly affects middle-aged and elderly people. Its progression begins with the degeneration of joint cartilage, gradually eroding the subchondral bone and surrounding tissues, causing synovitis, knee pain, limited movement and even deformities. At present, non-steroidal anti-inflammatory drugs can only relieve mild symptoms such as inflammation and pain, and joint replacement surgery is required in severe cases.

　　Although the FDA later approved stromal-associated autologous chondrocyte transplantation (MACI) therapy for repairing isolated cartilage injuries, there are obvious limitations of this therapy. Therefore, finding more efficient and wider range of articular cartilage progenitor cells and mechanisms to regulate their regeneration has become a key issue in the field of OA treatment.

　　On July 21, 2025, Professor Yue Rui's research team from the School of Life Sciences and Technology of Tongji University and the Institute of Regenerative Medicine of the Affiliated Oriental Hospital and Zou Weiguo of Hainan Medical University jointly published a research paper entitled "Procr⁺ chondroprogenitors sense mechanical stimuli to government artistic cartilage maintenance and regeneration" in Cell.

　　This study discovered the first time Procr⁺ chondrocytes that are sensitive to mechanical stimulation, and revealed a new mechanism by which Procr⁺ chondrocytes perceive mechanical stimulation regulates articular cartilage maintenance and regeneration.

　　Research background

　　In the study of articular cartilage progenitor cells, it is known that Prg4⁺ surface cells have cartilage progenitor cell activity and can differentiate into deep cartilage cells, but the heterogeneity and activation mechanism of these cells are still unclear; although Procr is a variety of adult tissue stem/progenitor cell markers, it is not clear whether it can be used as an adult articular cartilage progenitor cell marker.

　　At the same time, mechanical stimulation has a significant impact on the resting and activation of stem/progenitor cells in the musculoskeletal system. Mechanical sensitive proteins such as Piezo1 can transduce mechanical signals, but Piezo1-mediated mechanical responses are cell type-dependent. How articular cartilage progenitors perceive the specific mechanisms of mechanical stimulation to regulate cartilage production remains unclear.

　　In summary, there are two core problems in existing research: one is the lack of clear markers and sources of articular cartilage progenitor cells with efficient regeneration ability; the other is how mechanical stimulation regulates the activation and differentiation of cartilage progenitor cells to maintain cartilage homeostasis or promotes damage repair, and its molecular mechanism has not yet been clarified.

　　These problems constitute the starting point of this study, aiming to explore the potential of Procr + cells as articular cartilage progenitor cells and their perception mechanisms for mechanical stimulation, and provide new targets for the treatment of OA and cartilage defects.

　　Research content

　　First, the research team used genetic lineage tracing technology to hybridize Procr-CreERT2 mice with tdTomato reporter mice, and induce specific labeling of Procr⁺ cells through tamoxifen to track their distribution, differentiation fate and quantitative changes in articular cartilage and meniscus with age.

　　The results show that Procr⁺ cells are mainly located in the surface layer of the tibial articular cartilage and meniscus, and are a subgroup of Prg4⁺ surface cells. Their number is rich in puberty and gradually decreases with age. At the same time, they can differentiate into middle and deep chondrocytes in a time-dependent mode.

　　To explore the regulatory effect of mechanical stimulation on Procr⁺ cells, a mechanical loading and unloading model was constructed: 4-week-old Procr-CreERT2; tdTomato mice were subjected to 4-week mechanical loading (1 hour of forced exercise per day) or 4-week mechanical unloading (tail suspension), and combined with flow cytometry and fluorescence imaging to quantify the number of Procr⁺ cells.

　　The results showed that mechanical loading significantly increased the number of Procr⁺ cells in the tibia, femur and meniscus, while mechanical unloading significantly reduced the number of Procr⁺ cells in the tibia and meniscus, confirming that Procr⁺ cells are mechanically sensitive.

　　In the osteoarthritis (OA) model, OA was induced by medial meniscus instability (DMM) surgery, and Procr⁺ cells were activated, and their differentiation to the deep chondrocytes was significantly increased; after the specific knockdown of Procr⁺ cells by Procr-CreERT2; DTA mice, DMM-induced OA progress accelerated, manifested as increased OARSI score and increased osteophyte formation.

　　To analyze the molecular mechanism, single-cell RNA sequencing of chondrocytes from DMM and sham-operated mice was performed. Combined with regulatory network analysis (SCENIC), OA activates the Klf2-Ihh/Frzb pathway to promote Procr⁺ cell differentiation; intra-articular injection of Piezo1 inhibitor GsMTx4 or agonist Yoda1, combined with Procr⁺ cell-specific Piezo1 knockout mice (Procr-CreERT2; Piezo1fl/fl) showed that inhibition of Piezo1 blocked the cartilage regeneration function of Procr⁺ cells and aggravated OA, while activation of Piezo1 relieved OA symptoms, indicating that Piezo1 was Key molecules for mechanical signaling of Procr⁺Cells.

　　Finally, the researchers isolated and purified PROCR⁺ cells with similar properties from joint cartilage samples of young and elderly people, and proved that they had more robust cartilage repair capabilities compared with mature chondrocytes through in vivo transplantation experiments.