Developmental Regulation of the Growth Plate and Cranial Synchondrosis

Wei, Xiang; Hu, Min; Mishina, Yuji; Liu, F.

doi:10.1177/0022034516651823

Cited by 60 publications

(87 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Elevated ROS in growth plates of mice has previously been shown to disrupt the columnar proliferation of chondrocytes and their hypertrophic differentiation (Morita et al, 2007). Our data suggests that in addition to ROS-mediated effects on chondrogenesis, indirect, non-ROS mediated effects of chronic alcohol consumption on growth hormone/IGF-1 signaling (Badger et al, 1993; Srivastava et al 2002; Wang et al 2004); the calcium/Vitamin D axis (Shankar et al 2008a, Mercer et al, 2012) or effects on regulation of local growth factors in the growth plate such as Indian hedgehog, FGFs, or BMPs (Wei et al 2016) may also significantly impact bone lengthening.…”

Section: Discussionmentioning

confidence: 83%

Partial Protection by Dietary Antioxidants Against Ethanol‐Induced Osteopenia and Changes in Bone Morphology in Female Mice

Alund

Mercer

Pulliam

et al. 2016

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

Background Chronic alcohol consumption leads to increased fracture risk and an elevated risk of osteoporosis by decreasing bone accrual through increasing osteoclast activity and decreasing osteoblast activity. We have shown that this mechanism involves the generation of reactive oxygen species (ROS) produced by NADPH oxidases (NOX). It was hypothesized that different dietary antioxidants, N-acetyl cysteine (NAC, 1.2mg/kg/d) and α-tocopherol (VitE, 60 mg/kg/d)) would be able to attenuate the NOX-mediated ROS effects on bone due to chronic alcohol intake. Methods To study the effects of these antioxidants, female mice received a Lieber DeCarli liquid diet containing ethanol (EtOH) with or without additional antioxidant for 8 weeks. Results Tibias displayed decreased cortical bone mineral density in both the EtOH and EtOH+antioxidant groups compared to pair-fed (PF) and PF+antioxidant groups (P<0.05). However, there was significant protection from trabecular bone loss in mice fed either antioxidant (P<0.05). MicroCT analysis demonstrated a significant decrease in bone volume (BV/TV) and trabecular number (Tb.N) (P<0.05), along with a significant increase in trabecular spacing (Tb.Sp) in the EtOH compared to PF (P<0.05). In contrast, the EtOH+NAC and EtOH+α-tocopherol did not statistically differ from their respective PF controls. Ex vivo histological sections of tibias were stained for nitrotyrosine, an indicator of intracellular damage by ROS, and tibias from mice fed EtOH exhibited significantly more staining than PF controls. EtOH treatment significantly increased the number of marrow adipocytes per mm as well as mRNA expression of aP2, an adipocyte marker in bone. Only NAC was able to reduce the number of marrow adipocytes to PF levels. EtOH fed mice exhibited reduced bone length (P<0.05) and had a reduced number of proliferating chondrocytes within the growth plate. NAC and Vitamin E prevented this (P<0.05). Conclusions These data show that alcohol’s pathological effects on bone extend beyond decreasing bone mass and suggest a partial protective effect of the dietary antioxidants NAC and α-tocopherol at these doses with regard to alcohol effects on bone turnover and bone morphology.

show abstract

Section: Discussionmentioning

confidence: 83%

Partial Protection by Dietary Antioxidants Against Ethanol‐Induced Osteopenia and Changes in Bone Morphology in Female Mice

Alund

Mercer

Pulliam

et al. 2016

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

show abstract

“…Harris’ hematoxylin (VWR, Radnor, PA, 10143–606) and Eosin (VWR, 95057-848) staining proceeded by standard protocol. As the SOS is the last synchondrosis of the cranial base to fuse in humans, it is assumed that it has a greater impact on craniofacial development, thus we have focused on this region [12]. Three sections at least 30 μm apart were used for histomorphometric analysis.…”

Section: Methodsmentioning

confidence: 99%

“…These same processes are important for the craniofacial skeleton, as the synchondroses of the cranial base, like the growth plate in long bones, contribute to elongation by proliferation and hypertrophy of chondrocytes. Unlike long bone growth plates, the synchondroses produce growth in opposing directions [12]. …”

Section: Introductionmentioning

confidence: 99%

Thyroxine Exposure Effects on the Cranial Base

et al. 2017

View full text Add to dashboard Cite

Thyroid hormone is important for skull bone growth, which primarily occurs at the cranial sutures and synchondroses. Thyroid hormones regulate metabolism and act in all stages of cartilage and bone development and maintenance by interacting with growth hormone and regulating insulin-like growth factor. Aberrant thyroid hormone levels and exposure during development are exogenous factors that may exacerbate susceptibility to craniofacial abnormalities potentially through changes in growth at the synchondroses of the cranial base. To elucidate the direct effect of in utero therapeutic thyroxine exposure on the synchondroses in developing mice, we provided scaled doses of the thyroid replacement drug, levothyroxine in drinking water to pregnant C57BL6 wild-type dams. The skulls of resulting pups were subjected to microcomputed tomography analysis revealing less bone volume relative to tissue volume in the synchondroses of mouse pups exposed in utero to levothyroxine. Histological assessment of the cranial base area indicated more active synchondroses as measured by metabolic factors including Igf1. The cranial base of the pups exposed to high levels of levothyroxine also contained more collagen fiber matrix and an increase in markers of bone formation. Such changes due to exposure to exogenous thyroid hormone may drive overall morphological changes. Thus, excess thyroid hormone exposure to the fetus during pregnancy may lead to altered craniofacial growth and increased risk of anomalies in offspring.

show abstract

“…Prior research studies have demonstrated that long bones are formed through endochondral ossification of chondrocytes in which col2a1 is one of the most requisite matrix collagens (30). Thus, we hypothesized that the inhibition of BET bromodomain proteins may also affect the growth of the organism.…”

Section: I-bet151 and (ϩ)-Jq1mentioning

confidence: 95%

Bromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth

Niu

Shao

Yan

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Xiao-Fan WangSmall molecule inhibitors for bromodomain and extra-terminal (BET) proteins have recently emerged as potential therapeutic agents in clinical trials for various cancers. However, to date, it is unknown whether these inhibitors have side effects on bone structures. Here, we report that inhibition of BET bromodomain proteins may suppress chondrocyte differentiation and restrain bone growth. We generated a luciferase reporter system using the chondrogenic cell line ATDC5 in which the luciferase gene was driven by the promoter of Col2a1, an elementary collagen of the chondrocyte. The Col2a1-luciferase ATDC5 system was used for rapidly screening both activators and repressors of human collagen Col2a1 gene expression, and we found that BET bromodomain inhibitors reduce the Col2a1-luciferase. Consistent with the luciferase assay, BET inhibitors decrease the expression of Col2a1. Bromodomain and extra-terminal (BET)2 proteins (containing four mammalian members, BRD2, BRD3, BRD4, and BRDT) function as key epigenetic readers by recognizing histone acetylation through binding to ⑀-N-lysine acetylation motifs of histone, such as Lys-5, Lys-12, and Lys-16 residues of H4 histone (1, 2) and Lys-27 residues of H3 histone (3). The BET proteins interact with the positive transcription elongation factor P-TEF␤ and RNA polymerase II (Pol II) to facilitate gene transcription (4 -6). A list of drugs, such as I-BET151, I-BET762, PFI-1, and (ϩ)-JQ1, were discovered to target BET proteins and block the interaction between BET proteins and acetyl-lysine of histones (2, 7).BET proteins and BET inhibitors have been reported to be involved in a variety of biological processes. Pharmacological inhibition of BET proteins lowers the expression of key transcription factors such as oncogene c-MYC (8), clamps the transductions of PI3K signaling (9), inhibits Gli1 transcription and Hedgehog pathway (10), blocks transcription in neurons (11), represses VEGF-induced angiogenesis and vascular permeability (12), reduces cell viability of osteosarcoma cells and inhibits osteoblastic differentiation (13), and restrains osteoclastogenesis (14). Meanwhile, potent BET inhibitors have been identified as showing antitumor efficacy in a number of preclinical cancer models in recent years, including leukemia, multiple myeloma, lymphoma, melanoma, and gastric cancer (15,16). This led to clinical studies focusing mostly on the treatment of leukemia and lymphoma. As a result of these studies, the first encouraging signs of efficacy have already been reported (17). Furthermore, previous studies showed that BET inhibitors also control neuronal differentiation and cause an autism-like syndrome (18). However, BET inhibitors were not examined extensively in these studies to determine their side effects on skeletal bone structures.The long bone is mainly formed through endochondral bone formation, which starts with the formation of a cartilage template from condensed mesenchymal cells. The chondrocytes of the cartilage template proliferate axial...

show abstract

Developmental Regulation of the Growth Plate and Cranial Synchondrosis

Cited by 60 publications

References 59 publications

Partial Protection by Dietary Antioxidants Against Ethanol‐Induced Osteopenia and Changes in Bone Morphology in Female Mice

Partial Protection by Dietary Antioxidants Against Ethanol‐Induced Osteopenia and Changes in Bone Morphology in Female Mice

Thyroxine Exposure Effects on the Cranial Base

Bromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth

Contact Info

Product

Resources

About