Mesenchyme-specific knockout of ESET histone methyltransferase causes ectopic hypertrophy and terminal differentiation of articular chondrocytes.
The exact molecular mechanisms governing articular chondrocytes remain unknown in skeletal biology. In this study, we have found that ESET (an ERG-associated protein with a SET domain, also called SETDB1) histone methyltransferase is expressed in articular cartilage. To test whether ESET regulates articular chondrocytes, we carried out mesenchyme-specific deletion of the ESET gene in mice. ESET knock-out did not affect generation of articular chondrocytes during embryonic development. Two weeks after birth, there was minimal qualitative difference at the knee joints between wild-type and ESET knock-out animals. At 1 month, ectopic hypertrophy, proliferation, and apoptosis of articular chondrocytes were seen in the articular cartilage of ESET-null animals. At 3 months, additional signs of terminal differentiation such as increased alkaline phosphatase activity and an elevated level of matrix metalloproteinase (MMP)-13 were found in ESET-null cartilage. Staining for type II collagen and proteoglycan revealed that cartilage degeneration became progressively worse from 2 weeks to 12 months at the knee joints of ESET knock-out mutants. Analysis of over 14 pairs of age- and sex-matched wild-type and knock-out mice indicated that the articular chondrocyte phenotype in ESET-null mutants is 100% penetrant. Our results demonstrate that expression of ESET plays an essential role in the maintenance of articular cartilage by preventing articular chondrocytes from terminal differentiation and may have implications in joint diseases such as osteoarthritis.
From the Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington 98108.
Kevin A
KA
Lawson
From the Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington 98108.
Colin J
CJ
Teteak
From the Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington 98108.
Junhui
J
Zou
From the Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington 98108.
Jacques
J
Hacquebord
From the Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington 98108.
Andrew
A
Ghatan
From the Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington 98108.
Anna
A
Zielinska-Kwiatkowska
From the Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington 98108.
Russell J
RJ
Fernandes
From the Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington 98108; the Research and Development Program, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108.
Howard A
HA
Chansky
From the Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington 98108; the Research and Development Program, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108. Electronic address: lyang@u.washington.edu.
Liu
L
Yang
D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002358:Cartilage, Articular / Q000201:enzymology* / Q000473:pathology; D002454:Cell Differentiation; D019902:Chondrocytes / Q000201:enzymology* / Q000473:pathology; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006984:Hypertrophy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007719:Knee Joint / Q000201:enzymology* / Q000473:pathology; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D020370:Osteoarthritis, Knee / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
D024043:Collagen Type II; D011495:Histone-Lysine N-Methyltransferase; C516239:SETDB1 protein, mouse; D000469:Alkaline Phosphatase; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse
Arthritis; Articular cartilage; Cartilage biology; Chondrocytes; Differentiation; Epigenetics; Gene Knockout; Histone methylation