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2014 ; 29
(10
): 2262-75
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Epiphyseal chondrocyte secondary ossification centers require thyroid hormone
activation of Indian hedgehog and osterix signaling
#MMPMID24753031
Xing W
; Cheng S
; Wergedal J
; Mohan S
J Bone Miner Res
2014[Oct]; 29
(10
): 2262-75
PMID24753031
show ga
Thyroid hormones (THs) are known to regulate endochondral ossification during
skeletal development via acting directly in chondrocytes and osteoblasts. In this
study, we focused on TH effects on the secondary ossification center (SOC)
because the time of appearance of SOCs in several species coincides with the time
when peak levels of TH are attained. Accordingly, micro-computed tomography (µCT)
evaluation of femurs and tibias at day 21 in TH-deficient and control mice
revealed that endochondral ossification of SOCs is severely compromised owing to
TH deficiency and that TH treatment for 10 days completely rescued this
phenotype. Staining of cartilage and bone in the epiphysis revealed that whereas
all of the cartilage is converted into bone in the prepubertal control mice, this
conversion failed to occur in the TH-deficient mice. Immunohistochemistry studies
revealed that TH treatment of thyroid stimulating hormone receptor mutant
(Tshr(-/-) ) mice induced expression of Indian hedgehog (Ihh) and Osx in type 2
collagen (Col2)-expressing chondrocytes in the SOC at day 7, which subsequently
differentiate into type 10 collagen (Col10)/osteocalcin-expressing
chondro/osteoblasts at day 10. Consistent with these data, treatment of tibia
cultures from 3-day-old mice with 10 ng/mL TH increased expression of Osx, Col10,
alkaline phosphatase (ALP), and osteocalcin in the epiphysis by sixfold to
60-fold. Furthermore, knockdown of the TH-induced increase in Osx expression
using lentiviral small hairpin RNA (shRNA) significantly blocked TH-induced ALP
and osteocalcin expression in chondrocytes. Treatment of chondrogenic cells with
an Ihh inhibitor abolished chondro/osteoblast differentiation and SOC formation.
Our findings indicate that TH regulates the SOC initiation and progression via
differentiating chondrocytes into bone matrix-producing osteoblasts by
stimulating Ihh and Osx expression in chondrocytes.