Background/Purpose: Patients suffering from rheumatoid arthritis (RA) are often affected by fracture-healing complications such as increased fracture healing time or non-unions. There is not much information whether this is a result of the disease itself and/or its treatment with glucocorticoids (GC) and other immunomodulatory drugs. Previously, we have shown that immunologically restricted patients lack an adequate adaptation to hypoxia in the fracture hematoma facilitating healing disorders (Hoff et al. 2011 Immunol Res 51(1)). The hypoxic microenvironment during the initial fracture-healing phase is known to be essential for activating the immunological reactions which induce regeneration. The hypoxia-inducible factor (HIF) is one key regulator of cellular adaption to hypoxia that can be stabilized via different factors called in the following HIF-stabilizers. Therefore, we aimed at stabilizing the hypoxic phase by application of HIF-stabilizers to facilitate bone healing.  

Methods: A single-center retrospective study was conducted at the Charité University Hospital Berlin focusing on patients with long-bone fractures in order to identify factors which may affect the healing process. Obtained data were analyzed descriptively and statistically. In addition, we established an in vitro model simulating the inhibition of osteogenic mesenchymal stem cell (MSC) differentiation via high concentration GC treatment to test the counteracting potential of HIF-stabilizers. Furthermore, we performed an in vivoproof of concept study in a mouse osteotomy model (3 weeks, n=8 per group) evaluating the ratio of bone volume (BV) per total volume (TV) in the fracture gap using µCT. 

Results: 266 patients were included in the retrospective study, 79 cases (fracture healing disorders) and 178 controls. The descriptive analysis showed higher frequencies of GC (6.3% vs. 1.6%) and NSAID (7.6% vs. 2.7%) administration in patients with fracture healing disorders. Statistical analysis using logistic regression showed a high significance for RA (p=0.028) and a trend for smoking (p=0.075) to negatively affect fracture healing. In vitro, we observed a concentration-dependent inhibitory effect of dexamethasone on osteogenesis which could be considerably antagonized by HIF-stabilizers. Both optimal combinations and concentrations of HIF-stabilizers were tested in a mouse osteotomy model. As a result, HIF-stabilizers directly administered into the fracture gap at the time of the osteotomy showed a significant positive effect on healing processes as evidenced after 3 weeks by means of increased bony callus volume (BV/TV) compared to the respective vehicle controls. 

Conclusion: The results obtained so far support the hypothesis that RA indeed has a negative impact on the outcome of fracture healing. Our in vitro data demonstrate that HIF-stabilizers can be used to at least partially counteract the negative impact of high-dose GC on osseous differentiation. Finally, our in vivo data show a significant potential of HIF-stabilizers to facilitate bone healing. Therefore, this approach represents a promising strategy to prevent and overcome bone healing complications in RA patients and perhaps other immunologically restricted patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/immunological-dysregulation-and-inadequate-hypoxia-adaptation-hif-stabilization-as-possible-prevention-of-fracture-healing-disorders-in-ra-or-immune-suppressed-patients/