TY - JOUR
T1 - Critical roles of the TGF-β type I receptor ALK5 in perichondrial formation and function, cartilage integrity, and osteoblast differentiation during growth plate development
AU - Matsunobu, Tomoya
AU - Torigoe, Kiyoyuki
AU - Ishikawa, Masaki
AU - de Vega, Susana
AU - Kulkarni, Ashok B.
AU - Iwamoto, Yukihide
AU - Yamada, Yoshihiko
N1 - Funding Information:
We thank Drs. Stefan Karlsson, David M. Ornitz, and Andrew McMahon for ALK5-floxed mice, Dermo1-Cre mice, and CAGG- Cre-ER ™ mice, respectively. This work was supported by the Intramural Program of the NIDCR, National Institutes of Health. Tomoya Matsunobu was supported in part by a Fellowship from the Japan Society for the Promotion of Science.
PY - 2009/8/15
Y1 - 2009/8/15
N2 - TGF-β has been implicated in the proliferation and differentiation of chondrocytes and osteoblasts. However, the in vivo function of TGF-β in skeletal development is unclear. In this study, we investigated the role of TGF-β signaling in growth plate development by creating mice with a conditional knockout of the TGF-β type I receptor ALK5 (ALK5CKO) in skeletal progenitor cells using Dermo1-Cre mice. ALK5CKO mice had short and wide long bones, reduced bone collars, and trabecular bones. In ALK5CKO growth plates, chondrocytes proliferated and differentiated, but ectopic cartilaginous tissues protruded into the perichondrium. In normal growth plates, ALK5 protein was strongly expressed in perichondrial progenitor cells for osteoblasts, and in a thin chondrocyte layer located adjacent to the perichondrium in the peripheral cartilage. ALK5CKO growth plates had an abnormally thin perichondrial cell layer and reduced proliferation and differentiation of osteoblasts. These defects in the perichondrium likely caused the short bones and ectopic cartilaginous protrusions. Using tamoxifen-inducible Cre-ER™-mediated ALK5-deficient primary calvarial cell cultures, we found that TGF-β signaling promoted osteoprogenitor proliferation, early differentiation, and commitment to the osteoblastic lineage through the selective MAPKs and Smad2/3 pathways. These results demonstrate the important roles of TGF-β signaling in perichondrium formation and differentiation, as well as in growth plate integrity during skeletal development.
AB - TGF-β has been implicated in the proliferation and differentiation of chondrocytes and osteoblasts. However, the in vivo function of TGF-β in skeletal development is unclear. In this study, we investigated the role of TGF-β signaling in growth plate development by creating mice with a conditional knockout of the TGF-β type I receptor ALK5 (ALK5CKO) in skeletal progenitor cells using Dermo1-Cre mice. ALK5CKO mice had short and wide long bones, reduced bone collars, and trabecular bones. In ALK5CKO growth plates, chondrocytes proliferated and differentiated, but ectopic cartilaginous tissues protruded into the perichondrium. In normal growth plates, ALK5 protein was strongly expressed in perichondrial progenitor cells for osteoblasts, and in a thin chondrocyte layer located adjacent to the perichondrium in the peripheral cartilage. ALK5CKO growth plates had an abnormally thin perichondrial cell layer and reduced proliferation and differentiation of osteoblasts. These defects in the perichondrium likely caused the short bones and ectopic cartilaginous protrusions. Using tamoxifen-inducible Cre-ER™-mediated ALK5-deficient primary calvarial cell cultures, we found that TGF-β signaling promoted osteoprogenitor proliferation, early differentiation, and commitment to the osteoblastic lineage through the selective MAPKs and Smad2/3 pathways. These results demonstrate the important roles of TGF-β signaling in perichondrium formation and differentiation, as well as in growth plate integrity during skeletal development.
KW - ALK5 (TGF-β type I receptor)
KW - Chondrocytes
KW - Conditional knockout mice
KW - Growth plate
KW - Osteoblasts
KW - Perichondrium
KW - Skeletal progenitor cells
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U2 - 10.1016/j.ydbio.2009.06.002
DO - 10.1016/j.ydbio.2009.06.002
M3 - Article
C2 - 19501582
AN - SCOPUS:67650985957
VL - 332
SP - 325
EP - 338
JO - Developmental Biology
JF - Developmental Biology
SN - 0012-1606
IS - 2
ER -