TY - JOUR
T1 - Matrix metalloproteinase-9 is a diagnostic marker of heterotopic ossification in a murine model
AU - Rodenberg, Eric
AU - Azhdarinia, Ali
AU - Lazard, Zawaunyka W.
AU - Hall, Mary
AU - Kwon, Sun Kuk
AU - Wilganowski, Nathaniel
AU - Salisbury, Elizabeth A.
AU - Merched-Sauvage, Maria
AU - Olmsted-Davis, Elizabeth A.
AU - Sevick-Muraca, Eva M.
AU - Davis, Alan R.
PY - 2011/10/1
Y1 - 2011/10/1
N2 - Heterotopic ossification (HO) is a serious disorder that occurs when there is aberrant bone morphogenic protein (BMP) signaling in soft tissues. Currently, there are no methods to detect HO before mineralization occurs. Yet once mineralization occurs, there are no effective treatments, short of surgery, to reverse HO. Herein, we used in vivo molecular imaging and confirmatory ex vivo tissue analyses of an established murine animal model of BMP-induced HO to show that matrix metalloproteinase-9 (MMP-9) can be detected as an early-stage biomarker before mineralization. Ex vivo analyses show that active MMP-9 protein is significantly elevated within tissues undergoing HO as early as 48h after BMP induction, with its expression co-localizing to nerves and vessels. In vivo molecular imaging with a dual-labeled near-infrared fluorescence and micro-positron emission tomography (μPET) agent specific to MMP-2/-9 expression paralleled the ex vivo observations and reflected the site of HO formation as detected from microcomputed tomography 7 days later. The results suggest that the MMP-9 is a biomarker of the early extracellular matrix (ECM) re-organization and could be used as an in vivo diagnostic with confirmatory ex vivo tissue analysis for detecting HO or conversely for monitoring the success of tissue-engineered bone implants that employ ECM biology for engraftment.
AB - Heterotopic ossification (HO) is a serious disorder that occurs when there is aberrant bone morphogenic protein (BMP) signaling in soft tissues. Currently, there are no methods to detect HO before mineralization occurs. Yet once mineralization occurs, there are no effective treatments, short of surgery, to reverse HO. Herein, we used in vivo molecular imaging and confirmatory ex vivo tissue analyses of an established murine animal model of BMP-induced HO to show that matrix metalloproteinase-9 (MMP-9) can be detected as an early-stage biomarker before mineralization. Ex vivo analyses show that active MMP-9 protein is significantly elevated within tissues undergoing HO as early as 48h after BMP induction, with its expression co-localizing to nerves and vessels. In vivo molecular imaging with a dual-labeled near-infrared fluorescence and micro-positron emission tomography (μPET) agent specific to MMP-2/-9 expression paralleled the ex vivo observations and reflected the site of HO formation as detected from microcomputed tomography 7 days later. The results suggest that the MMP-9 is a biomarker of the early extracellular matrix (ECM) re-organization and could be used as an in vivo diagnostic with confirmatory ex vivo tissue analysis for detecting HO or conversely for monitoring the success of tissue-engineered bone implants that employ ECM biology for engraftment.
UR - http://www.scopus.com/inward/record.url?scp=80053128756&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053128756&partnerID=8YFLogxK
U2 - 10.1089/ten.tea.2011.0007
DO - 10.1089/ten.tea.2011.0007
M3 - Article
C2 - 21599541
AN - SCOPUS:80053128756
SN - 1937-3341
VL - 17
SP - 2487
EP - 2496
JO - Tissue Engineering - Part A.
JF - Tissue Engineering - Part A.
IS - 19-20
ER -