# Effect of Blood on Synovial Joint Tissues: Potential Role of Ferroptosis
## 8 Conclusions  
This review highlights the prevalence of blood-induced arthropathies as a result of traumatic knee injuries or congenital disorders. A better understanding of the impact of blood on synovial joint tissues will support research efforts aimed at mitigating blood-induced joint damage, such as the development of prophylactic treatments of disease-borne, trauma- and iatrogenic-induced joint bleeding. Toward these efforts, biofelic in vitro models can offer well-defined experimental platforms to complement in vivo models [141]. Co-culture models that include the synovium, which envelops the joint, with other tissue(s) in the knee may provide additional information regarding tissue crosstalk and help to identify complementary therapeutic targets to mitigate the contribution of joint bleeding to the development of arthropathy [79]. The incorporation of mechanical loading that may exacerbate joint degeneration, by providing physical stimuli or enhanced solute transport, may further provide a more physiologic context to study blood and synovial joint tissue interactions [142; 143; 144]. Blood-injured cartilage, for example, has been reported to be less capable to withstand loading in vivo [53; 55]. Additionally, the study of blood and its behavior in synovial fluid may also be an important consideration [77]. These culture models may also permit the optimization of adjunctive therapies, such as corticosteroids, or the application of pulsed electromagnetic fields (PEMFs) [105; 106; 145].  
Our findings, from investigating blood co-culture with chondrocytes, lead us to suggest that ferrotposis plays a crucial role in HA development and could result in adverse effects on joint tissues [14]. While ferrotposis has been shown to contribute to blood-induced cartilage degenerative changes, its role in modulating tissue changes to the synovium, meniscus, ligament, and bone remains to be determined. In this context, as previously mentioned, Fer-1 is a potent and selective inhibitor of ferrotposis that acts by suppressing lipid peroxidation through lipophilic peroxyl radical trapping activity [11]. However, Fer-1's ADME properties make it challenging to use in animal models. New Fer-1 analogs, with improved potency and metabolic and plasma stability, would lay the foundation for a new therapeutic approach to treating these patients and other related blood-based conditions involving ferrotposis.  
Current research investigating the role of the interaction of blood with synovial tissues is primarily focused on cartilage and chondrocytes as cartilage degeneration is the leading comorbidity. Additional research is necessary to understand the contribution of joint bleeding to changes in the maintenance and repair capacity of other synovial joint tissues like the synovium, meniscus, bone, and ligament. Our data suggest that ferrotposis may represent a therapeutic target with regard to joint degeneration associated with joint bleeding. The application of experimental in vitro and in vivo models of hemarthrosis, as reviewed herein, may help to inform the development of therapeutic treatments for synovial joint bleeding.  
Conceptualization, H.J.N.III and C.T.H.; writing--original draft preparation, H.J.N.III, C.T.H., N.S., A.J.L., J.R., I.G.O. and R.S.; writing--review and editing, H.J.N.III, C.T.H., N.S., J.R., I.G.O., R.S., N.O.C., G.A.A. and R.P.S. All authors contributed significantly to the studies reported in this manuscript. All authors have read and agreed to the published version of the manuscript.  
This work was supported in part by funding from NIH 5P41 EB027062 (TERC), NIH R01 AR077760, an NSF graduate research fellowship (N.S., H.J.N.III), and the Orthopedic Science and Research Foundation.