Analysis of the trajectory of osteoarthritis development in a mouse model by serial near-infrared fluorescence imaging of matrix metalloproteinase activities.
OBJECTIVE
A major hurdle in osteoarthritis (OA) research is the lack of sensitive detection and monitoring methods. It is hypothesized that proteases, such as matrix metalloproteinases (MMPs), are up-regulated in the early stages of OA development. This study was undertaken to investigate if a near-infrared (NIR) fluorescent probe activated by MMPs could visualize in vivo OA progression beginning in the early stages of the disease.


METHODS
Using an MMP-activatable NIR fluorescent probe (MMPSense 680), we assessed the up-regulation of MMP activity in vitro by incubating human chondrocytes with the proinflammatory cytokine interleukin-1β (IL-1β). MMP activity was then evaluated in vivo serially in a mouse model of chronic, injury-induced OA. To track MMP activity over time, mice were imaged 1-8 weeks after OA-inducing surgery. Imaging results were correlated with histologic findings.


RESULTS
In vitro studies confirmed that NIR fluorescence imaging identified enhanced MMP activity in IL-1β-treated human chondrocytes. In vivo imaging showed significantly higher fluorescence intensity in OA knees compared to sham-operated (control) knees of the same mice. Additionally, the total emitted fluorescence intensity steadily increased over the entire course of OA progression that was examined. NIR fluorescence imaging results correlated with histologic findings, which showed an increase in articular cartilage structural damage over time.


CONCLUSIONS
Imaging of MMP activity in a mouse model of OA provides sensitive and consistent visualization of OA progression, beginning in the early stages of OA. In addition to facilitating the preclinical study of OA modulators, this approach has the potential for future translation to humans.
Tufts University, Boston, Massachusetts.
Averi A
AA
Leahy
Shadi A
SA
Esfahani
Andrea T
AT
Foote
Carrie K
CK
Hui
Roshni S
RS
Rainbow
Daisy S
DS
Nakamura
Brian H
BH
Tracey
Umar
U
Mahmood
Li
L
Zeng
D000818:Animals; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008592:Menisci, Tibial / Q000601:surgery; D051379:Mice; D008815:Mice, Inbred Strains; D061848:Optical Imaging / Q000379:methods*; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D012680:Sensitivity and Specificity
D053583:Interleukin-1beta; D020782:Matrix Metalloproteinases