scholarly journals Regulation of terminal hypertrophic chondrocyte differentiation in Prmt5 mutant mice modeling infantile idiopathic scoliosis

2019 ◽  
Author(s):  
Zhaoyang Liu ◽  
Janani Ramachandran ◽  
Steven A Vokes ◽  
Ryan S Gray
Keyword(s):  
Bone Formation ◽  
Idiopathic Scoliosis ◽  
Age Of Onset ◽  
Endochondral Bone Formation ◽  
Chondrocyte Differentiation ◽  
Respiratory Compromise ◽  
Endochondral Bone ◽  
Hypertrophic Chondrocyte ◽  
Infantile Idiopathic Scoliosis ◽  
Adult Spine

ABSTRACTIdiopathic scoliosis (IS) is the most common type of musculoskeletal defect effecting children and is classified by age of onset, location, and degree of spine curvature. Although rare, the onset of IS during infancy is the more severe and rapidly progressive form of the disease, leading to increased mortality due to significant respiratory compromise. The pathophysiology of IS, in particular for infantile IS, remain elusive. Here, we show that PRMT5 is critical for the regulation of terminal hypertrophic chondrocyte differentiation in the spine and models infantile IS in mouse. Conditional ablation of PRMT5 in osteochondral progenitors led to impaired terminal hypertrophic chondrocyte differentiation and asymmetric defects of endochondral bone formation in the perinatal spine. Analysis of several markers of endochondral ossification revealed increased COLX and Ihh expression and a dramatic reduction of Mmp13 and RUNX2 expression in the intervertebral disc and vertebral growth plate. Furthermore, we demonstrate that PRMT5 function in committed chondrogenic lineages is required for regulation of COLX expression in the adult spine. Together, our results establish PRMT5 as a critical regulator of hypertrophic chondrocyte differentiation and endochondral bone formation in spine development and maintenance.

scholarly journals Dmrt2 promotes transition of endochondral bone formation by linking Sox9 and Runx2

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Koichiro Ono ◽  
Kenji Hata ◽  
Eriko Nakamura ◽  
Shota Ishihara ◽  
Sachi Kobayashi ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Bone Formation ◽  
Skeletal Development ◽  
Endochondral Bone Formation ◽  
Chondrocyte Differentiation ◽  
Endochondral Bone ◽  
Chondrocyte Hypertrophy ◽  
Hypertrophic Chondrocyte ◽  
Delayed Initiation ◽  
Related Transcription Factor

AbstractEndochondral bone formation is fundamental for skeletal development. During this process, chondrocytes undergo multiple steps of differentiation and coordinated transition from a proliferating to a hypertrophic stage, which is critical to advance skeletal development. Here, we identified the transcription factor Dmrt2 (double-sex and mab-3 related transcription factor 2) as a Sox9-inducible gene that promotes chondrocyte hypertrophy in pre-hypertrophic chondrocytes. Epigenetic analysis further demonstrated that Sox9 regulates Dmrt2 expression through an active enhancer located 18 kb upstream of the Dmrt2 gene and that this enhancer’s chromatin status is progressively activated through chondrocyte differentiation. Dmrt2-knockout mice exhibited a dwarf phenotype with delayed initiation of chondrocyte hypertrophy. Dmrt2 augmented hypertrophic chondrocyte gene expression including Ihh through physical and functional interaction with Runx2. Furthermore, Dmrt2 deficiency reduced Runx2-dependent Ihh expression. Our findings suggest that Dmrt2 is critical for sequential chondrocyte differentiation during endochondral bone formation and coordinates the transcriptional network between Sox9 and Runx2.

scholarly journals Prolyl Hydroxylase Domain-Containing Protein 3 Gene Expression in Chondrocytes Is Not Essential for Bone Development in Mice

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2200
Author(s):  
Weirong Xing ◽  
Sheila Pourteymoor ◽  
Gustavo A. Gomez ◽  
Yian Chen ◽  
Subburaman Mohan
Keyword(s):  
Gene Expression ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Bone Volume ◽  
Endochondral Bone Formation ◽  
Chondrocyte Differentiation ◽  
Trabecular Bone Volume ◽  
Endochondral Bone ◽  
Trabecular Bone Mass

We previously showed that conditional disruption of the Phd2 gene in chondrocytes led to a massive increase in long bone trabecular bone mass. Loss of Phd2 gene expression or inhibition of PHD2 activity by a specific inhibitor resulted in a several-fold compensatory increase in Phd3 expression in chondrocytes. To determine if expression of PHD3 plays a role in endochondral bone formation, we conditionally disrupted the Phd3 gene in chondrocytes by crossing Phd3 floxed (Phd3flox/flox) mice with Col2α1-Cre mice. Loss of Phd3 expression in the chondrocytes of Cre+; Phd3flox/flox conditional knockout (cKO) mice was confirmed by real time PCR. At 16 weeks of age, neither body weight nor body length was significantly different in the Phd3 cKO mice compared to Cre−; Phd3flox/flox wild-type (WT) mice. Areal BMD measurements of total body as well as femur, tibia, and lumbar skeletal sites were not significantly different between the cKO and WT mice at 16 weeks of age. Micro-CT measurements revealed significant gender differences in the trabecular bone volume adjusted for tissue volume at the secondary spongiosa of the femur and the tibia for both genotypes, but no genotype difference was found for any of the trabecular bone measurements of either the femur or the tibia. Trabecular bone volume of distal femur epiphysis was not different between cKO and WT mice. Histology analyses revealed Phd3 cKO mice exhibited a comparable chondrocyte differentiation and proliferation, as evidenced by no changes in cartilage thickness and area in the cKO mice as compared to WT littermates. Consistent with the in vivo data, lentiviral shRNA-mediated knockdown of Phd3 expression in chondrocytes did not affect the expression of markers of chondrocyte differentiation (Col2, Col10, Acan, Sox9). Our study found that Phd2 but not Phd3 expressed in chondrocytes regulates endochondral bone formation, and the compensatory increase in Phd3 expression in the chondrocytes of Phd2 cKO mice is not the cause for increased trabecular bone mass in Phd2 cKO mice.

scholarly journals ADAMTS-7, a Direct Target of PTHrP, Adversely Regulates Endochondral Bone Growth by Associating with and Inactivating GEP Growth Factor

2009 ◽  
Vol 29 (15) ◽  
pp. 4201-4219 ◽  
Author(s):  
Xiao-Hui Bai ◽  
Da-Wei Wang ◽  
Li Kong ◽  
Yan Zhang ◽  
Yi Luan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Bone Formation ◽  
Proteolytic Activity ◽  
Bone Growth ◽  
Endochondral Bone Formation ◽  
Chondrocyte Differentiation ◽  
Growth Plate Chondrocytes ◽  
Endochondral Bone ◽  
Direct Target

ABSTRACT ADAMTS-7, a metalloproteinase that belongs to ADAMTS family, is important for the degradation of cartilage extracellular matrix proteins in arthritis. Herein we report that ADAMTS-7 is upregulated during chondrocyte differentiation and demonstrates the temporal and spatial expression pattern during skeletal development. ADAMTS-7 potently inhibits chondrocyte differentiation and endochondral bone formation, and this inhibition depends on its proteolytic activity. The cysteine-rich domain of ADAMTS-7 is required for its interaction with the extracellular matrix, and the C-terminal four-thrombospondin motifs are necessary for its full proteolytic activity and inhibition of chondrocyte differentiation. ADAMTS-7 is an important target of canonical PTHrP signaling, since (i) PTHrP induces ADAMTS-7, (ii) ADAMTS-7 is downregulated in PTHrP null mutant (PTHrP−/−) growth plate chondrocytes, and (iii) blockage of ADAMTS-7 almost abolishes PTHrP-mediated inhibition of chondrocyte hypertrophy and endochondral bone growth. ADAMTS-7 associates with granulin-epithelin precursor (GEP), an autocrine growth factor that has been implicated in tissue regeneration, tumorigenesis, and inflammation. In addition, ADAMTS-7 acts as a new GEP convertase and neutralizes GEP-stimulated endochondral bone formation. Collectively, these findings demonstrate that ADAMTS-7, a direct target of PTHrP signaling, negatively regulates endochondral bone formation by associating with and inactivating GEP chondrogenic growth factor.

scholarly journals Constitutive E2F1 Overexpression Delays Endochondral Bone Formation by Inhibiting Chondrocyte Differentiation

2003 ◽  
Vol 23 (10) ◽  
pp. 3656-3668 ◽  
Author(s):  
Blanca Scheijen ◽  
Marieke Bronk ◽  
Tiffany van der Meer ◽  
René Bernards
Keyword(s):  
Bone Formation ◽  
Endochondral Ossification ◽  
Bone Growth ◽  
Late Phase ◽  
Type Ii Collagen ◽  
Endochondral Bone Formation ◽  
Nodule Formation ◽  
Chondrocyte Differentiation ◽  
Endochondral Bone ◽  
Chondrocyte Maturation

ABSTRACT Longitudinal bone growth results from endochondral ossification, a process that requires proliferation and differentiation of chondrocytes. It has been shown that proper endochondral bone formation is critically dependent on the retinoblastoma family members p107 and p130. However, the precise functional roles played by individual E2F proteins remain poorly understood. Using both constitutive and conditional E2F1 transgenic mice, we show that ubiquitous transgene-driven expression of E2F1 during embryonic development results in a dwarf phenotype and significantly reduced postnatal viability. Overexpression of E2F1 disturbs chondrocyte maturation, resulting in delayed endochondral ossification, which is characterized by reduced hypertrophic zones and disorganized growth plates. Employing the chondrogenic cell line ATDC5, we investigated the effects of enforced E2F expression on the different phases of chondrocyte maturation that are normally required for endochondral ossification. Ectopic E2F1 expression strongly inhibits early- and late-phase differentiation of ATDC5 cells, accompanied by diminished cartilage nodule formation as well as decreased type II collagen, type X collagen, and aggrecan gene expression. In contrast, overexpression of E2F2 or E2F3a results in only a marginal delay of chondrocyte maturation, and increased E2F4 levels have no effect. These data are consistent with the notion that E2F1 is a regulator of chondrocyte differentiation.

XBP1S Induces GEP and Enhances Endochondral Bone Growth

2014 ◽  
Vol 926-930 ◽  
pp. 1136-1139
Author(s):  
Feng Jin Guo ◽  
Rong Jiang ◽  
Xiao Feng Han
Keyword(s):  
Growth Factor ◽  
Bone Formation ◽  
Bone Growth ◽  
Ex Vivo ◽  
Skeletal Development ◽  
Endochondral Bone Formation ◽  
Chondrocyte Differentiation ◽  
Endochondral Bone ◽  
Temporal And Spatial

We previously reported that transcription factor XBP1S is upregulated during chondrocyte differentiation and demonstrates the temporal and spatial expression pattern during skeletal development. Herein, we found that XBP1S stimulates chondrocyte differentiation from mesenchymal stem cells in vitro and endochondral ossification ex vivo. In addition, XBP1S activates granulin-epithelin precursor (GEP), a growth factor known to stimulate chondrogenesis, then enhances GEP-stimulated chondrogenesis and endochondral bone formation. Collectively, these findings demonstrate that XBP1S positively regulates endochondral bone formation by activating GEP chondrogenic growth factor.

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