# Effect of Blood on Synovial Joint Tissues: Potential Role of Ferroptosis
## 4 In Vitro Models
### Cartilage  
Blood has been shown to induce rapid and irreversible damage to cartilage that is characteristic of degeneration observed in the early stages of osteoarthritis (OA) [86; 87; 88; 86]. Alarmingly, short exposure to a low amount of blood (10% \(\
u\)/\(\
u\) for 48 h) leads to prolonged and irreversible disturbances in cartilage matrix turnover still present ten weeks after initial  
\begin{table}
\begin{tabular}{|c|c c c|} \hline  & **Reference** & **Experimental Design** & **Research Findings** \\ \hline SYNOVIUM & [PERSON] et al., 2019 [80] & Compare effects of blood-derived products and sodium hyaluron on equine synovial fluid cells from osteochondotic joint [80] & All treatments decreased production of reactive oxygen species. PRP increased prostaglandin (PG) E\({}_{2}\) concentrations and PRP, APP, and IRAP increased IL-1 receptor antagonist proteins [80] \\ \hline MENISCUS & & Acute controlled response of meniscus cells exposed to various concentrations of whole blood for 3 days to simulate injury [82] & Autologous blood exposure did not affect meniscal cell viability but blood + DEX [81] & meniscal cell viability but blood + DEX treatment reduced cell viability suggesting that meniscal cells may be susceptible to glucocorticoid-mediated apoptosis. [81] \\ \hline MENISCUS & & Porcine explants and primary meniscus cells exposed to various concentrations of whole blood for 3 days to simulate injury [82] & Acute whole blood exposure increased MMP MMP activity. Blood-derived mononuclear leukocytes increased NO release and MMP activity but decreased GAG content suggesting that they activate catabolic pathways that can lead to meniscal degradation. Isolated intact RBC did not affect meniscus catabolism. [82] \\ \hline BONE & & Assess potential of menarthrosis-derived cells to differentiate into osteoblast-like cells via gene expression and osteeoblastic markers [83] & Osteoblastic gene markers significantly increased in hemorrhosis-derived cells in comparison to control and cell morphology was cuboidal shaped. Human hemarthrosis-derived cells contain osteeoprogenitor cells and can be used for bone regeneration [83] \\ \hline BONE & & Rats were subjected to noninvasive ACL rupture. Whole blood MSC concentration was assessed using flow cytometry and synovial fluid and serum were assayed for stromal cell-derived factor (SDF-1a) [84] & Following ACL rupture, there was a significant increase in bone marrow-derived MSC concentration and SDF-1a. Cell tracking indicated active recruitment of MSCs to the injured joint. [84] \\ \hline BONE & & Measure effects of platelets and erythrocytes on cytokine release and scaffold contraction in a 3D fibroblast model [14] & Platelet concentration significantly affects fibroblast proliferation, cytokine release, and gel contraction [14] \\ \hline ACL & & & Greater scaffold contraction and fibroblast proliferation of samples with RBC concentrations lower than that in whole blood. Increasing RBC concentration over amount in whole blood stimulates fibroblast collagen production and decreases scaffold contraction. [13] \\ \hline \multirow{6}{*}{ACL} & & & Co-culture of PBMCs and ACL fibroblasts without presence of platelets had no effect. PBMCs + platelet exposure led to an (PBMCs) on 3D ACL fibroblast collagen scaffold [85] & Co-culture of PBMCs and ACL fibroblasts without presence of platelets had no effect. PBMCs + platelet exposure led to an (PBMCs) on 3D ACL fibroblast collagen scaffold [85] & \\ \cline{1  
blood exposure; the blood concentration in the synovial cavity reaches nearly 100% during hemarthrosis episodes as a result of the small synovial fluid volume [10; 52; 61]. Recent studies by our group reported that intact RBCs induce intracellular phenotypic changes in chondrocytes that increase vulnerability to tissue damage while lysed red blood cells have a more direct influence on chondrocyte death (Figure 4A) by mechanisms that are representative of ferroptosis [14].