Chondrogenic progenitor cells respond to cartilage injury.
OBJECTIVE
Hypocellularity resulting from chondrocyte death in the aftermath of mechanical injury is thought to contribute to posttraumatic osteoarthritis. However, we observed that nonviable areas in cartilage injured by blunt impact were repopulated within 7-14 days by cells that appeared to migrate from the surrounding matrix. The aim of this study was to assess our hypothesis that the migrating cell population included chondrogenic progenitor cells that were drawn to injured cartilage by alarmins.


METHODS
Osteochondral explants obtained from mature cattle were injured by blunt impact or scratching, resulting in localized chondrocyte death. Injured sites were serially imaged by confocal microscopy, and migrating cells were evaluated for chondrogenic progenitor characteristics. Chemotaxis assays were used to measure the responses to chemokines, injury-conditioned medium, dead cell debris, and high mobility group box chromosomal protein 1 (HMGB-1).


RESULTS
Migrating cells were highly clonogenic and multipotent and expressed markers associated with chondrogenic progenitor cells. Compared with chondrocytes, these cells overexpressed genes involved in proliferation and migration and underexpressed cartilage matrix genes. They were more active than chondrocytes in chemotaxis assays and responded to cell lysates, conditioned medium, and HMGB-1. Glycyrrhizin, a chelator of HMGB-1 and a blocking antibody to receptor for advanced glycation end products (RAGE), inhibited responses to cell debris and conditioned medium and reduced the numbers of migrating cells on injured explants.


CONCLUSIONS
Injuries that caused chondrocyte death stimulated the emergence and homing of chondrogenic progenitor cells, in part via HMGB-1 release and RAGE-mediated chemotaxis. Their repopulation of the matrix could promote the repair of chondral damage that might otherwise contribute to progressive cartilage loss.
Dongrim Seol, PhD, Daniel J. McCabe, BS, Hyeonghun Choe, ME, Hongjun Zheng, PhD, Yin Yu, BM, Keewoong Jang, MS, Morgan W. Walter, BS, Abigail D. Lehman, BS, Lei Ding, PhD, James A. Martin, PhD: University of Iowa, Iowa City.
Dongrim
D
Seol
Dongrim Seol, PhD, Daniel J. McCabe, BS, Hyeonghun Choe, ME, Hongjun Zheng, PhD, Yin Yu, BM, Keewoong Jang, MS, Morgan W. Walter, BS, Abigail D. Lehman, BS, Lei Ding, PhD, James A. Martin, PhD: University of Iowa, Iowa City.
Daniel J
DJ
McCabe
Dongrim Seol, PhD, Daniel J. McCabe, BS, Hyeonghun Choe, ME, Hongjun Zheng, PhD, Yin Yu, BM, Keewoong Jang, MS, Morgan W. Walter, BS, Abigail D. Lehman, BS, Lei Ding, PhD, James A. Martin, PhD: University of Iowa, Iowa City.
Hyeonghun
H
Choe
Dongrim Seol, PhD, Daniel J. McCabe, BS, Hyeonghun Choe, ME, Hongjun Zheng, PhD, Yin Yu, BM, Keewoong Jang, MS, Morgan W. Walter, BS, Abigail D. Lehman, BS, Lei Ding, PhD, James A. Martin, PhD: University of Iowa, Iowa City.
Hongjun
H
Zheng
Dongrim Seol, PhD, Daniel J. McCabe, BS, Hyeonghun Choe, ME, Hongjun Zheng, PhD, Yin Yu, BM, Keewoong Jang, MS, Morgan W. Walter, BS, Abigail D. Lehman, BS, Lei Ding, PhD, James A. Martin, PhD: University of Iowa, Iowa City.
Yin
Y
Yu
Dongrim Seol, PhD, Daniel J. McCabe, BS, Hyeonghun Choe, ME, Hongjun Zheng, PhD, Yin Yu, BM, Keewoong Jang, MS, Morgan W. Walter, BS, Abigail D. Lehman, BS, Lei Ding, PhD, James A. Martin, PhD: University of Iowa, Iowa City.
Keewoong
K
Jang
Dongrim Seol, PhD, Daniel J. McCabe, BS, Hyeonghun Choe, ME, Hongjun Zheng, PhD, Yin Yu, BM, Keewoong Jang, MS, Morgan W. Walter, BS, Abigail D. Lehman, BS, Lei Ding, PhD, James A. Martin, PhD: University of Iowa, Iowa City.
Morgan W
MW
Walter
Dongrim Seol, PhD, Daniel J. McCabe, BS, Hyeonghun Choe, ME, Hongjun Zheng, PhD, Yin Yu, BM, Keewoong Jang, MS, Morgan W. Walter, BS, Abigail D. Lehman, BS, Lei Ding, PhD, James A. Martin, PhD: University of Iowa, Iowa City.
Abigail D
AD
Lehman
Dongrim Seol, PhD, Daniel J. McCabe, BS, Hyeonghun Choe, ME, Hongjun Zheng, PhD, Yin Yu, BM, Keewoong Jang, MS, Morgan W. Walter, BS, Abigail D. Lehman, BS, Lei Ding, PhD, James A. Martin, PhD: University of Iowa, Iowa City.
Lei
L
Ding
Joseph A. Buckwalter, MD: University of Iowa and VA Medical Center, Iowa City, Iowa.
Joseph A
JA
Buckwalter
Dongrim Seol, PhD, Daniel J. McCabe, BS, Hyeonghun Choe, ME, Hongjun Zheng, PhD, Yin Yu, BM, Keewoong Jang, MS, Morgan W. Walter, BS, Abigail D. Lehman, BS, Lei Ding, PhD, James A. Martin, PhD: University of Iowa, Iowa City.
James A
JA
Martin
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002358:Cartilage, Articular / Q000293:injuries* / Q000473:pathology; D002417:Cattle; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000502:physiology; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000502:physiology; D020370:Osteoarthritis, Knee / Q000209:etiology / Q000473:pathology*; D013264:Stifle / Q000293:injuries* / Q000473:pathology; D059467:Transcriptome; D014949:Wounds, Nonpenetrating / Q000473:pathology