Wnt/β-catenin Signaling Regulates Cranial Base Development and Growth

2008 ◽  
Vol 87 (3) ◽  
pp. 244-249 ◽  
Author(s):  
M. Nagayama ◽  
M. Iwamoto ◽  
A. Hargett ◽  
N. Kamiya ◽  
Y. Tamamura ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Wnt Signaling ◽  
Growth Plate ◽  
Endochondral Ossification ◽  
Cranial Base ◽  
Developmental Changes ◽  
Chondrocyte Hypertrophy ◽  
Chondrocyte Maturation ◽  
Wnt Proteins ◽  
Deficient Mice

Wnt proteins and β-catenin signaling regulate major processes during embryonic development, and we hypothesized that they regulate cranial base synchondrosis development and growth. To address this issue, we analyzed cartilage-specific β -catenin-deficient mice. Mutant synchondroses lacked typical growth plate zones, and endochondral ossification was delayed. In reciprocal transgenic experiments, cartilage overexpression of a constitutive active Lef1, a transcriptional mediator of Wnt/β-catenin signaling, caused precocious chondrocyte hypertrophy and intermingling of immature and mature chondrocytes. The developmental changes seen in β -catenin-deficient synchondroses were accompanied by marked reductions in Ihh and PTHrP as well as sFRP-1, an endogenous Wnt signaling antagonist and a potential Ihh signaling target. Thus, Wnt/β-catenin signaling is essential for cranial base development and synchondrosis growth plate function. This pathway promotes chondrocyte maturation and ossification events, and may exert this important role by dampening the effects of Ihh-PTHrP together with sFRP-1.

TBX1 Regulates Chondrocyte Maturation in the Spheno-occipital Synchondrosis

2020 ◽  
Vol 99 (10) ◽  
pp. 1182-1191 ◽  
Author(s):  
N. Funato ◽  
D. Srivastava ◽  
S. Shibata ◽  
H. Yanagisawa
Keyword(s):  
Digeorge Syndrome ◽  
Endochondral Ossification ◽  
Transcriptional Activity ◽  
Ectopic Expression ◽  
Chondrocyte Differentiation ◽  
Craniofacial Skeleton ◽  
Chondrocyte Maturation ◽  
Expression Of Genes ◽  
Growth Center ◽  
Deficient Mice

The synchondrosis in the cranial base is an important growth center for the craniofacial region. Abnormalities in the synchondroses affect the development of adjacent regions, including the craniofacial skeleton. Here, we report that the transcription factor TBX1, the candidate gene for DiGeorge syndrome, is expressed in mesoderm-derived chondrocytes and plays an essential and specific role in spheno-occipital synchondrosis development by inhibiting the expression of genes involved in chondrocyte hypertrophy and osteogenesis. In Tbx1-deficient mice, the spheno-occipital synchondrosis was completely mineralized at birth. TBX1 interacts with RUNX2, a master molecule of osteoblastogenesis and a regulator of chondrocyte maturation, and suppresses its transcriptional activity. Indeed, deleting Tbx1 triggers accelerated mineralization due to accelerated chondrocyte differentiation, which is associated with ectopic expression of downstream targets of RUNX2 in the spheno-occipital synchondrosis. These findings reveal that TBX1 acts as a regulator of chondrocyte maturation and osteogenesis during the spheno-occipital synchondrosis development. Thus, the tight regulation of endochondral ossification by TBX1 is crucial for the normal progression of chondrocyte differentiation in the spheno-occipital synchondrosis.

scholarly journals PH domain and leucine rich repeat phosphatase 1 (Phlpp1) suppresses parathyroid hormone receptor 1 (Pth1r) expression and signaling during bone growth

2020 ◽  
Author(s):  
Samantha R. Weaver ◽  
Earnest L. Taylor ◽  
Elizabeth L. Zars ◽  
Katherine M. Arnold ◽  
Elizabeth W. Bradley ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Growth Plate ◽  
Endochondral Ossification ◽  
Bone Growth ◽  
Long Bone ◽  
Leucine Rich Repeat ◽  
Ph Domain ◽  
Mineral Density ◽  
Longitudinal Bone Growth ◽  
Deficient Mice

ABSTRACTEndochondral ossification is tightly controlled by a coordinated network of signaling cascades including parathyroid hormone (PTH). PH domain and leucine rich repeat phosphatase (Phlpp1) affects endochondral ossification by suppressing chondrocyte proliferation in the growth plate, longitudinal bone growth, and bone mineralization. As such, Phlpp1−/− mice have shorter long bones, thicker growth plates, and proportionally larger growth plate proliferative zones. The goal of this study was to determine how Phlpp1 deficiency affects PTH signaling during bone growth. Transcriptomic analysis revealed greater Pth1r expression and H3K27ac enrichment at the Pth1r promoter in Phlpp1-deficient chondrocytes. PTH(1-34) enhanced and PTH(7-34) attenuated cell proliferation, cAMP signaling, CREB phosphorylation, and cell metabolic activity in Phlpp1-inhibited chondrocytes. To understand the role of Pth1r action in the endochondral phenotypes of Phlpp1-deficient mice, Phlpp1−/− mice were injected with Pth1r ligand PTH(7-34) daily for the first four weeks of life. PTH(7-34) reversed the abnormal growth plate and long bone growth phenotypes of Phlpp1−/− mice but did not rescue deficits in bone mineral density or trabecular number. These results demonstrate that elevated Pth1r expression and signaling contributes to increased proliferation in Phlpp1−/− chondrocytes and shorter bones in Phlpp1-deficient mice. Our data reveal a novel molecular relationship between Phlpp1 and Pth1r in chondrocytes during growth plate development and longitudinal bone growth.

scholarly journals Innovative Three-Dimensional Microscopic Analysis of Uremic Growth Plate Discloses Alterations in the Process of Chondrocyte Hypertrophy: Effects of Growth Hormone Treatment

2020 ◽  
Vol 21 (12) ◽  
pp. 4519
Author(s):  
Ángela Fernández-Iglesias ◽  
Rocío Fuente ◽  
Helena Gil-Peña ◽  
Laura Alonso-Durán ◽  
María García-Bengoa ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Plate ◽  
Growth Hormone Treatment ◽  
Three Dimensional ◽  
Microscopic Analysis ◽  
Hormone Treatment ◽  
Gh Treatment ◽  
Chondrocyte Hypertrophy ◽  
Chondrocyte Maturation ◽  
And Function

Chronic kidney disease (CKD) alters the morphology and function of the growth plate (GP) of long bones by disturbing chondrocyte maturation. GP chondrocytes were analyzed in growth-retarded young rats with CKD induced by adenine intake (AD), control rats fed ad libitum (C) or pair-fed with the AD group (PF), and CKD rats treated with growth hormone (ADGH). In order to study the alterations in the process of GP maturation, we applied a procedure recently described by our group to obtain high-quality three-dimensional images of whole chondrocytes that can be used to analyze quantitative parameters like cytoplasm density, cell volume, and shape. The final chondrocyte volume was found to be decreased in AD rats, but GH treatment was able to normalize it. The pattern of variation in the cell cytoplasm density suggests that uremia could be causing a delay to the beginning of the chondrocyte hypertrophy process. Growth hormone treatment appears to be able to compensate for this disturbance by triggering an early chondrocyte enlargement that may be mediated by Nkcc1 action, an important membrane cotransporter in the GP chondrocyte enlargement.

scholarly journals The Skull’s Girder: A Brief Review of the Cranial Base

2021 ◽  
Vol 9 (1) ◽  
pp. 3
Author(s):  
Shankar Rengasamy Venugopalan ◽  
Eric Van Otterloo
Keyword(s):  
Birth Defects ◽  
Vertebral Column ◽  
Endochondral Ossification ◽  
Cranial Base ◽  
Facial Skeleton ◽  
The Core ◽  
Skull Vault ◽  
Congenital Birth Defects ◽  
Intimate Association ◽  
The Brain

The cranial base is a multifunctional bony platform within the core of the cranium, spanning rostral to caudal ends. This structure provides support for the brain and skull vault above, serves as a link between the head and the vertebral column below, and seamlessly integrates with the facial skeleton at its rostral end. Unique from the majority of the cranial skeleton, the cranial base develops from a cartilage intermediate—the chondrocranium—through the process of endochondral ossification. Owing to the intimate association of the cranial base with nearly all aspects of the head, congenital birth defects impacting these structures often coincide with anomalies of the cranial base. Despite this critical importance, studies investigating the genetic control of cranial base development and associated disorders lags in comparison to other craniofacial structures. Here, we highlight and review developmental and genetic aspects of the cranial base, including its transition from cartilage to bone, dual embryological origins, and vignettes of transcription factors controlling its formation.

L-type calcium channels in growth plate chondrocytes participate in endochondral ossification

2007 ◽  
Vol 101 (2) ◽  
pp. 389-398 ◽  
Author(s):  
Edna E. Mancilla ◽  
Mario Galindo ◽  
Barbara Fertilio ◽  
Mario Herrera ◽  
Karime Salas ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Growth Plate ◽  
Endochondral Ossification ◽  
Growth Plate Chondrocytes

scholarly journals Thyroid Hormone Enhances Aggrecanase-2/ADAM-TS5 Expression and Proteoglycan Degradation in Growth Plate Cartilage

Endocrinology ◽  
2003 ◽  
Vol 144 (6) ◽  
pp. 2480-2488 ◽  
Author(s):  
Seicho Makihira ◽  
Weiqun Yan ◽  
Hiroshi Murakami ◽  
Masae Furukawa ◽  
Toshihisa Kawai ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Growth Plate ◽  
Cleavage Site ◽  
Endochondral Ossification ◽  
Core Protein ◽  
Binding Capacity ◽  
Mrna Level ◽  
Cartilage Explants ◽  
Type I ◽  
Proteoglycan Degradation

Abstract Effects of thyroid hormone on proteoglycan degradation in various regions of cartilage were investigated. In propylthiouracil-treated rats with hypothyroidism, proteoglycan degradation in epiphyseal cartilage during endochondral ossification was markedly suppressed. However, injections of T4 reversed this effect of propylthiouracil on proteoglycan degradation. In pig growth plate explants, T3 also induced breakdown of proteoglycan. T3 increased the release of aggrecan monomer and core protein from the explants into the medium. Accordingly, the level of aggrecan monomer remaining in the tissue decreased after T3 treatment, and the monomer lost hyaluronic acid-binding capacity, suggesting that the cleavage site is in the interglobular domain. The aggrecan fragment released from the T3-exposed explants underwent cleavage at Glu373-Ala374, the major aggrecanase-cleavage site. The stimulation of proteoglycan degradation by T3 was less prominent in resting cartilage explants than in growth plate explants and was barely detectable in articular cartilage explants. Using rabbit growth plate chondrocyte cultures, we explored proteases that may be involved in T3-induced aggrecan degradation and found that T3 enhanced the expression of aggrecanase-2/ADAM-TS5 (a disintegrin and a metalloproteinase domain with thrombospondin type I domains) mRNA, whereas we could not detect any enhancement of stromelysin, gelatinase, or collagenase activities or any aggrecanase-1/ADAM-TS4 mRNA expression. We also found that the aggrecanse-2 mRNA level, but not aggrecanase-1, increased at the hypertrophic stage during endochondral ossification. These findings suggest that aggrecanse-2/ADAM-TS5 is involved in aggrecan breakdown during endochondral ossification, and that thyroid hormone stimulates the aggrecan breakdown partly via the enhancement of aggrecanase-2/ADAM-TS5.

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