Influence of osteoarthritis grade on molecular signature of human cartilage.
Articular chondrocytes maintain cartilage matrix turnover and have the capacity for anabolic and catabolic activities that can be influenced by injury and disease. This study tested the hypothesis that catabolic genes are upregulated with regional osteoarthritis (OA) disease severity within a joint. With IRB approval, specimens of knee cartilage obtained as discarded tissues from subjects undergoing arthroplasty were partitioned for each subject by OA disease severity and evaluated for gene expression by RT-PCR. There was regional OA grade-associated upregulation of expected inflammatory mediators TNF-α, TNF receptors, IFN-γ, and interleukins as well as genes encoding proteolytic enzymes, including Adamts-5 and MMPs. Osteoclast-related genes, cathepsin K, tartrate-resistant acid phosphatase (TRAP), RANKL, RANK, M-CSF, and c-fms, but not osteoprotegerin, were induced in advanced grades. In vitro treatment of normal human chondrocytes with interleukin-1β upregulated similar genes; this provides evidence that chondrocytes per se can be the source of osteoclast-related factors. Immunohistochemical staining showed that RANK- and RANKL-positive cells were abundant in advanced grades, especially in chondrocyte clusters. This suggests a possible autocrine mechanism by which an osteoclast phenotype is induced in articular chondrocytes. In sum, these studies identified gene expression signatures in human OA cartilage based upon regional disease severity within a joint. There was an effect of OA Grade on expression of osteoclastic lytic enzymes and regulatory factors in human articular chondrocytes. Induction of an osteoclast-like phenotype in chondrocytes may be part of OA progression and suggests specific therapeutic approaches.
Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts.
Shuanhu
S
Zhou
Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Thomas S
TS
Thornhill
Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Fangang
F
Meng
Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Li
L
Xie
Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
John
J
Wright
Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Department of Oral and Maxillofacial Surgery, Harvard School of Dental Medicine, Boston, Massachusetts.
Julie
J
Glowacki
D000328:Adult; D000368:Aged; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D053583:Interleukin-1beta; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D053583:Interleukin-1beta
cartilage; inflammation; osteoarthritis; osteoclastogenesis; proteolytic enzymes