Don't hedge your bets: Hedgehog signaling as a central mediator of endochondral bone development and cartilage diseases

2011 ◽  
Vol 29 (6) ◽  
pp. 810-815 ◽  
Author(s):  
Jason S. Rockel ◽  
Benjamin A. Alman
Keyword(s):  
Hedgehog Signaling ◽  
Bone Development ◽  
Endochondral Bone ◽  
Cartilage Diseases ◽  
And Cartilage

scholarly journals Site-1 protease is essential for endochondral bone formation in mice

2007 ◽  
Vol 179 (4) ◽  
pp. 687-700 ◽  
Author(s):  
Debabrata Patra ◽  
Xiaoyun Xing ◽  
Sherri Davies ◽  
Jennifer Bryan ◽  
Carl Franz ◽  
...  
Keyword(s):  
Er Stress ◽  
Hedgehog Signaling ◽  
Endochondral Ossification ◽  
Bone Development ◽  
Active Form ◽  
Type Ii Collagen ◽  
Chondrocyte Apoptosis ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Er Stress Response

Site-1 protease (S1P) has an essential function in the conversion of latent, membrane-bound transcription factors to their free, active form. In mammals, abundant expression of S1P in chondrocytes suggests an involvement in chondrocyte function. To determine the requirement of S1P in cartilage and bone development, we have created cartilage-specific S1P knockout mice (S1Pcko). S1Pcko mice exhibit chondrodysplasia and a complete lack of endochondral ossification even though Runx2 expression, Indian hedgehog signaling, and osteoblastogenesis is intact. However, there is a substantial increase in chondrocyte apoptosis in the cartilage of S1Pcko mice. Extraction of type II collagen is substantially lower from S1Pcko cartilage. In S1Pcko mice, the collagen network is disorganized and collagen becomes entrapped in chondrocytes. Ultrastructural analysis reveals that the endoplasmic reticulum (ER) in S1Pcko chondrocytes is engorged and fragmented in a manner characteristic of severe ER stress. These data suggest that S1P activity is necessary for a specialized ER stress response required by chondrocytes for the genesis of normal cartilage and thus endochondral ossification.

scholarly journals Smpd3Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development

2016 ◽  
Vol 36 (17) ◽  
pp. 2282-2299 ◽  
Author(s):  
Jingjing Li ◽  
Garthiga Manickam ◽  
Seemun Ray ◽  
Chun-do Oh ◽  
Hideyo Yasuda ◽  
...  
Keyword(s):  
Bone Development ◽  
Skeletal Development ◽  
Loss Of Function ◽  
Endochondral Bone ◽  
Transgenic Expression ◽  
Phosphodiesterase 3 ◽  
Skeletal Phenotype ◽  
Metabolizing Enzyme ◽  
Bone Abnormalities ◽  
And Cartilage

Sphingomyelin phosphodiesterase 3 (SMPD3), a lipid-metabolizing enzyme present in bone and cartilage, has been identified to be a key regulator of skeletal development. A homozygous loss-of-function mutation called fragilitas ossium (fro) in theSmpd3gene causes poor bone and cartilage mineralization resulting in severe congenital skeletal deformities. Here we show thatSmpd3expression in ATDC5 chondrogenic cells is downregulated by parathyroid hormone-related peptide through transcription factor SOX9. Furthermore, we show that transgenic expression ofSmpd3in the chondrocytes offro/fromice corrects the cartilage but not the bone abnormalities. Additionally, we report the generation ofSmpd3flox/floxmice for the tissue-specific inactivation ofSmpd3using the Cre-loxPsystem. We found that the skeletal phenotype inSmpd3flox/flox; Osx-Cremice, in which theSmpd3gene is ablated in both late-stage chondrocytes and osteoblasts, closely mimics the skeletal phenotype infro/fromice. On the other hand,Smpd3flox/flox;Col2a1-Cremice, in which theSmpd3gene is knocked out in chondrocytes only, recapitulate thefro/fromouse cartilage phenotype. This work demonstrates thatSmpd3expression in both chondrocytes and osteoblasts is required for normal endochondral bone development.

Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation

Development ◽  
2001 ◽  
Vol 128 (24) ◽  
pp. 5099-5108 ◽  
Author(s):  
Fanxin Long ◽  
Xiaoyan M. Zhang ◽  
Seth Karp ◽  
Yingzi Yang ◽  
Andrew P. McMahon
Keyword(s):  
Cyclin D1 ◽  
Hedgehog Signaling ◽  
Genetic Manipulation ◽  
Bone Development ◽  
Transmembrane Protein ◽  
Wild Type ◽  
Chondrocyte Proliferation ◽  
Direct Role ◽  
Endochondral Bone ◽  
Proliferation And Differentiation

Indian hedgehog (Ihh), one of the three mammalian hedgehog (Hh) proteins, coordinates proliferation and differentiation of chondrocytes during endochondral bone development. Smoothened (Smo) is a transmembrane protein that transduces all Hh signals. In order to discern the direct versus indirect roles of Ihh in cartilage development, we have used the Cre-loxP approach to remove Smo activity specifically in chondrocytes. Animals generated by this means develop shorter long bones when compared to wild-type littermates. In contrast to Ihh mutants (Ihhn/Ihhn), chondrocyte differentiation proceeds normally. However, like Ihhn/Ihhn mice, proliferation of chondrocytes is reduced by about 50%, supporting a direct role for Ihh in the regulation of chondrocyte proliferation. Moreover, by overexpressing either Ihh or a constitutively active Smo allele (Smo*) specifically in the cartilage using the bigenic UAS-Gal4 system, we demonstrate that activation of the Ihh signaling pathway is sufficient to promote chondrocyte proliferation. Finally, expression of cyclin D1 is markedly downregulated when either Ihh or Smo activity is removed from chondrocytes, indicating that Ihh regulates chondrocyte proliferation at least in part by modulating the transcription of cyclin D1. Taken together, the present study establishes Ihh as a key mitogen in the endochondral skeleton.

scholarly journals Microarray Analyses of Gene Expression during Chondrocyte Differentiation Identifies Novel Regulators of Hypertrophy

2005 ◽  
Vol 16 (11) ◽  
pp. 5316-5333 ◽  
Author(s):  
Claudine G. James ◽  
C. Thomas G. Appleton ◽  
Veronica Ulici ◽  
T. Michael Underhill ◽  
Frank Beier
Keyword(s):  
Gene Expression ◽  
Bone Development ◽  
Skeletal Development ◽  
Expression Patterns ◽  
Chondrocyte Differentiation ◽  
Endochondral Bone ◽  
Temporal Gene Expression ◽  
Affymetrix Microarrays ◽  
Time Period ◽  
And Cluster Analysis

Ordered chondrocyte differentiation and maturation is required for normal skeletal development, but the intracellular pathways regulating this process remain largely unclear. We used Affymetrix microarrays to examine temporal gene expression patterns during chondrogenic differentiation in a mouse micromass culture system. Robust normalization of the data identified 3300 differentially expressed probe sets, which corresponds to 1772, 481, and 249 probe sets exhibiting minimum 2-, 5-, and 10-fold changes over the time period, respectively. GeneOntology annotations for molecular function show changes in the expression of molecules involved in transcriptional regulation and signal transduction among others. The expression of identified markers was confirmed by RT-PCR, and cluster analysis revealed groups of coexpressed transcripts. One gene that was up-regulated at later stages of chondrocyte differentiation was Rgs2. Overexpression of Rgs2 in the chondrogenic cell line ATDC5 resulted in accelerated hypertrophic differentiation, thus providing functional validation of microarray data. Collectively, these analyses provide novel information on the temporal expression of molecules regulating endochondral bone development.

Isolation, Culture and Identification of Bovine Skeletal Stem Cells

2021 ◽  
Vol 11 (12) ◽  
pp. 2337-2345
Author(s):  
Junhui Lai ◽  
Qin Yang ◽  
Ruining Liang ◽  
Weijun Guan ◽  
Xiuxia Li
Keyword(s):  
Stem Cells ◽  
Cell Surface ◽  
Bone Formation ◽  
Growth Plate ◽  
Bone Development ◽  
Long Bone ◽  
Biological Characterization ◽  
Self Renewal ◽  
And Cartilage

The growth plate is essential in long bone formation and contains a wealth of skeletal stem cells (SSCs). Though the origin and the mechanism for SSCs generation remain uncertain, recent studies demonstrate the transition from cartilage to bone that in the lineage for bone development. SSCs possesses the ability to differentiate into bone and cartilage in vitro. In this research, we aimed to isolate and culture the skeletal stem cells from bovine cattle and then studied its biological characterization. The results showed that these bovine SSCs are positive for PDPN+CD73+CD164+CD90+CD44+ cell surface bio-markers, they are capable of self-renewal and differentiation. Our dates proved that SSCs exists in bovine’s long bone.

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