SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice.
Chondrocyte hypertrophy is crucial for endochondral ossification, but the mechanism underlying this process is not fully understood. We report that salt-inducible kinase 3 (SIK3) deficiency causes severe inhibition of chondrocyte hypertrophy in mice. SIK3-deficient mice showed dwarfism as they aged, whereas body size was unaffected during embryogenesis. Anatomical and histological analyses revealed marked expansion of the growth plate and articular cartilage regions in the limbs, accumulation of chondrocytes in the sternum, ribs and spine, and impaired skull bone formation in SIK3-deficient mice. The primary phenotype in the skeletal tissue of SIK3-deficient mice was in the humerus at E14.5, where chondrocyte hypertrophy was markedly delayed. Chondrocyte hypertrophy was severely blocked until E18.5, and the proliferative chondrocytes occupied the inside of the humerus. Consistent with impaired chondrocyte hypertrophy in SIK3-deficient mice, native SIK3 expression was detected in the cytoplasm of prehypertrophic and hypertrophic chondrocytes in developing bones in embryos and in the growth plates in postnatal mice. HDAC4, a crucial repressor of chondrocyte hypertrophy, remained in the nuclei in SIK3-deficient chondrocytes, but was localized in the cytoplasm in wild-type hypertrophic chondrocytes. Molecular and cellular analyses demonstrated that SIK3 was required for anchoring HDAC4 in the cytoplasm, thereby releasing MEF2C, a crucial facilitator of chondrocyte hypertrophy, from suppression by HDAC4 in nuclei. Chondrocyte-specific overexpression of SIK3 induced closure of growth plates in adulthood, and the SIK3-deficient cartilage phenotype was rescued by transgenic SIK3 expression in the humerus. These results demonstrate an essential role for SIK3 in facilitating chondrocyte hypertrophy during skeletogenesis and growth plate maintenance.
Department of Bone and Cartilage Biology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Satoru
S
Sasagawa
Hiroshi
H
Takemori
Tatsuya
T
Uebi
Daisuke
D
Ikegami
Kunihiko
K
Hiramatsu
Shiro
S
Ikegawa
Hideki
H
Yoshikawa
Noriyuki
N
Tsumaki
D000818:Animals; D001846:Bone Development / Q000235:genetics; D001842:Bone and Bones / Q000002:abnormalities; D002454:Cell Differentiation / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000502:physiology*; D020219:Chondrogenesis; D024161:Collagen Type XI / Q000235:genetics; D004392:Dwarfism / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D006132:Growth Plate / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism; D006984:Hypertrophy; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018006:Myogenic Regulatory Factors / Q000096:biosynthesis; D010012:Osteogenesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
C497046:Col11a2 protein, mouse; D024161:Collagen Type XI; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D017346:Protein Serine-Threonine Kinases; C571369:SIK3 protein, mouse; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases