Targeting angiogenesis for fracture nonunion treatment in inflammatory disease

Cuicui Wang,Gaurav Swarnkar,Jun Ying,Jie Shen,Ding Xiao,Tianhong Zhou,Jianjun Guan,Xiaolei Nie,Yousef Abu-Amer

doi:10.1038/s41413-021-00150-4

Abstract

Atrophic fracture nonunion poses a significant clinical problem with limited therapeutic interventions. In this study, we developed a unique nonunion model with high clinical relevance using serum transfer-induced rheumatoid arthritis (RA). Arthritic mice displayed fracture nonunion with the absence of fracture callus, diminished angiogenesis and fibrotic scar tissue formation leading to the failure of biomechanical properties, representing the major manifestations of atrophic nonunion in the clinic. Mechanistically, we demonstrated that the angiogenesis defect observed in RA mice was due to the downregulation of SPP1 and CXCL12 in chondrocytes, as evidenced by the restoration of angiogenesis upon SPP1 and CXCL12 treatment in vitro. In this regard, we developed a biodegradable scaffold loaded with SPP1 and CXCL12, which displayed a beneficial effect on angiogenesis and fracture repair in mice despite the presence of inflammation. Hence, these findings strongly suggest that the sustained release of SPP1 and CXCL12 represents an effective therapeutic approach to treat impaired angiogenesis and fracture nonunion under inflammatory conditions.

Highlights

INTRODUCTION Approximately ten percent of the16 million fractures that occur annually in the United States do not progress to timely union and exhibit prolonged healing or nonunion.[1,2] There are two distinct types of fracture nonunion characterized by different radiographical observations and biological properties, atrophic and hypertrophic nonunion.[3]
Unbiased in vitro screen of angiogenic factors, we found that secreted phosphoprotein 1 (SPP1) and C-X-C motif chemokine Inflammation reduced the expression of angiogenic factors and ligand 12 (CXCL12) are the two factors downregulated to the impaired angiogenesis in mice greatest extent by IL-1β treatment, suggesting SPP1 and CXCL12 as potential targets of inflammation in chondrocytes
We found a gradual increase in new SPP1 and CXCL12 restored angiogenesis in inflammation in vitro bone formation around the fracture area by 14 dpf in the control Since SPP1, the most abundantly expressed factor in chondrocytes, mice

Summary

RESULTS

Systemic inflammation had adverse effects on the expression of Elevated inflammation led to fracture nonunion in RA mice The rising global prevalence of inflammatory diseases, especially RA,[51,52,53] is associated with debilitating comorbidities and clinical complications, including delayed fracture union and nonunion.[8,54,55] To examine the effect of inflammation/RA on fracture angiogenic factors, leading to reduced angiogenesis during fracture repair. Our in vivo finding demonstrated that the RA mice developed impaired angiogenesis due to inflammation, which led properties by the torsion test and found that the maximum bone us to speculate that the reduced angiogenic factors, but not VEGF, strength in the RA mice treated with SPP1 and CXCL12 was significantly restored by 28 dpf (Fig. 6h) These findings strongly suggest that the local release of SPP1 and CXCL12 via PCL scaffolds represents an effective therapeutic approach to are likely the direct downstream targets that mediate the reduced angiogenesis observed in vivo.

DISCUSSION

Findings

METHODS