This is a Hiroki Yokota study who along with Ping Zhang is one of the prime developers of lateral loading modalities.
Generation of the Chondroprotective Proteomes by Activating PI3K and TNFα Signaling
“Chondrosarcoma and inflammatory arthritis are two joint-damaging diseases. Here, we examined whether a counterintuitive approach of activating tumorigenic and inflammatory signaling may generate joint-protective proteomes in mesenchymal stem cells and chondrocytes for the treatment of chondrosarcoma and inflammatory arthritis{we already kind of know that low levels of inflammatory signaling is beneficial, it’s too much that’s the problem}. While activating PI3K signaling and the administration of TNFα to chondrosarcoma cells and chondrocytes promoted tumor progression and inflammatory responses, those cells paradoxically generated a chondroprotective conditioned medium. Notably, the chondroprotective conditioned medium was enriched with Hsp90ab1 that interacted with GAPDH. Extracellular GAPDH interacted with L1CAM, an oncogenic transmembrane protein, and inhibited tumorigenic behaviors, whereas intracellular GAPDH downregulated p38 in chondrocytes and exerted anti-inflammatory effects. The result supports the unconventional approach of generating chondroprotective proteomes.”
“We employed mesenchymal stem cells and chondrocytes to generate chondroprotective proteomes{proteomes are essentially a collection of proteins} by activating PI3K signaling and the administration of TNFα.”
“In response to chemotherapeutic agents, the reverse behavior of resilient cancer cells is frequently observed. While their tumorigenic action may initially be suppressed, cells tend to develop drug resistance and gradually strengthen their progression”
“Chronic inflammation is reported to facilitate tumor progression, while the induction of inflammation may contribute to suppressing tumorigenesis by stimulating immune responses”
“Besides chondrocyte-derived CM, MSC-derived CM, as well as MH7a synovial cell-derived CM, were converted to tumor suppressive by the treatment with YS49, an activator of PI3K signaling. Their application reduced the level of TNFα and MMP13 in C28/I2 chondrocytes”
“Hsp90ab1, a heat shock protein acting as a molecular chaperon, showed the most pronounced anti-inflammatory effect in C28 chondrocytes by downregulating TNFα and MMP13”
” the chondroprotective proteome can be generated from MSCs and chondrocytes by activating PI3K signaling with YS49 and treating them with TNFα. When switched on, both PI3K and TNFα signalings acted tumorigenic in CS cells and inflammatory in chondrocytes. However, YS49 and TNFα converted skeletal host cells such as MSCs and chondrocytes into iTSCs and iISCs, and they generated tumor-suppressive and inflammation-suppressive CMs. We observed that YS49 and TNFα-treated CMs inhibited the proliferation, migration, and invasion of CS cells. Those CMs downregulated Runx2 and MMP9 in CS cells, as well as NFATc1 and cathepsin K in osteoclasts, whereas they decreased TNFα and MMP13 in chondrocytes”