Connexin 43 Channels Are Essential for Normal Bone Structure and Osteocyte Viability

Xu, Huiyun; Gu, Sumin; Riquelme, Manuel A.; Burra, Sirisha; Callaway, Danielle; Cheng, Hongyun; Guda, Teja; Schmitz, James E.; Fajardo, Roberto J.; Werner, Sherry L.; Zhao, Hong; Shang, Peng; Johnson, Mark; Bonewald, Lynda F.; Jiang, Jean X.

doi:10.1002/jbmr.2374

Cited by 96 publications

(123 citation statements)

References 44 publications

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“…Up to 30% unoccupied osteocyte lacunae have been observed in cortical bone of Cx43 conditional knockout mice (Bivi et al, 2012a;Lloyd et al, 2014;Xu et al, 2015). Despite the nearly identical cortical bone phenotype observed in the Gja1 −/K258Stop and Cx43 conditional knockout models, we did not detect any difference in empty lacunae between groups, suggesting that osteocytic apoptosis does not precede the phenotype, at least in male Gja1 −/K258Stop mice.…”

Section: Discussioncontrasting

confidence: 64%

“…4D). As osteocyte apoptosis has been implicated as one of the mechanisms of the effects of Cx43 on bone (Bivi et al, 2012a;Xu et al, 2015), empty and occupied osteocyte lacunae were counted in cortical bone for mice of each genotype. The percentage of occupied osteocyte lacunae was unaffected by Cx43 CT truncation (Fig.…”

Section: Altered Bone Formation Rates In Male Gja1mentioning

confidence: 99%

“…−/K258Stop mice Osteoblast-lineage-specific Cx43 deletion has been shown to indirectly affect osteoclast-mediated bone resorption via the RANKL and OPG pathway, an effect that contributes to the expansion of the marrow cavity in those models (Bivi et al, 2012a;Lloyd et al, 2013;Watkins et al, 2011Watkins et al, , 2012Xu et al, 2015;Zhang et al, 2011). Accordingly, we looked at RANKL and OPG mRNA levels in RNA extracts from tibial extracts by qRT-PCR (Fig.…”

Section: Enhanced Bone Resorption In Male Gja1mentioning

confidence: 99%

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Defective signaling, osteoblastogenesis and bone remodeling in a mouse model of connexin 43 C-terminal truncation

Moorer

Hebert

Tomlinson

et al. 2017

Journal of Cell Science

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In skeletal tissue, loss or mutation of the gap junction protein connexin 43 (Cx43, also known as GJA1) in cells of the osteoblast lineage leads to a profound cortical bone phenotype and defective tissue remodeling. There is mounting evidence in bone cells that the C-terminus (CT) of Cx43 is a docking platform for signaling effectors and is required for efficient downstream signaling. Here, we examined this function, using a mouse model of Cx43 CT-truncation (Gja1 K258Stop). Relative to Gja1 +/− controls, male Gja1 −/K258Stop mice have a cortical bone phenotype that is remarkably similar to those reported for deletion of the entire Cx43 gene in osteoblasts. Furthermore, we show that the Cx43 CT binds several signaling proteins that are required for optimal osteoblast function, including PKCδ, ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) and β-catenin. Deletion of the Cx43 CT domain affects these signaling cascades, impacting osteoblast proliferation, differentiation, and collagen processing and organization. These data imply that, at least in bone, Cx43 gap junctions not only exchange signals, but also recruit the appropriate effector molecules to the Cx43 CT in order to efficiently activate signaling cascades that affect cell function and bone acquisition.

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Section: Discussioncontrasting

confidence: 64%

Section: Altered Bone Formation Rates In Male Gja1mentioning

confidence: 99%

Section: Enhanced Bone Resorption In Male Gja1mentioning

confidence: 99%

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Defective signaling, osteoblastogenesis and bone remodeling in a mouse model of connexin 43 C-terminal truncation

Moorer

Hebert

Tomlinson

et al. 2017

Journal of Cell Science

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“…However, other evidence suggests that inhibiting this communication can enhance bone formation during loading High-resolution 3D imaging of osteocyte anatomy and pathology and preserve it during unloading, which is reviewed by Lloyd and colleagues (2014). Recent studies have shown that the osteocyte gap junction channel Connexin 43 plays an integral role in bone mechanobiology and osteocyte viability (Plotkin et al, 2015;Riquelme et al, 2015;Xu et al, 2015). Primary cilia.…”

Section: Onandlcn At the Ultrastructural Levelmentioning

confidence: 99%

“…Recent studies have shown that the osteocyte gap junction channel Connexin 43 plays an integral role in bone mechanobiology and osteocyte viability (Plotkin et al, 2015;Riquelme et al, 2015;Xu et al, 2015). Primary cilia.…”

Section: Pm Goggin Et Almentioning

confidence: 99%

High-resolution 3D imaging of osteocytes and computational modelling in mechanobiology: insights on bone development, ageing, health and disease

Goggin

Zygalakis

Oreffo³

et al. 2016

eCM

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Osteocytes are involved in mechanosensation and mechanotransduction in bone and hence, are key to bone adaptation in response to development, ageing and disease. Thus, detailed knowledge of the three-dimensional (3D) structure of the osteocyte network (ON) and the surrounding lacuno-canalicular network (LCN) is essential. Enhanced understanding of the ON&LCN will contribute to a better understanding of bone mechanics on cellular and sub-cellular scales, for instance through improved computational models of bone mechanotransduction. Until now, the location of the ON within the hard bone matrix and the sub-µm dimensions of the ON&LCN have posed significant challenges for 3D imaging. This review identifies relevant microstructural phenotypes of the ON&LCN in health and disease and summarises how light microscopy, electron microscopy and X-ray imaging techniques have been used in studies of osteocyte anatomy, pathology and mechanobiology to date. In this review, we assess the requirements for ON&LCN imaging and examine the state of the art in the fields of imaging and computational modelling as well as recent advances in high-resolution 3D imaging. Suggestions for future investigations using volume electron microscopy are indicated and we present new data on the ON&LCN using serial block-face scanning electron microscopy. A correlative approach using these high-resolution 3D imaging techniques in conjunction with in silico modelling in bone mechanobiology will increase understanding of osteocyte function and, ultimately, lead to improved pathways for diagnosis and treatment of bone diseases such as osteoporosis.Keywords: Osteocyte, 3D imaging, microscopy, b i o m e c h a n i c s , l a c u n o -c a n a l i c u l a r n e t w o r k , mechanobiology, mechanosensation, mechanotransduction, osteoporosis. IntroductionThrough bone adaptation, the skeleton adapts continuously to changed mechanical loading patterns due to development, growth, ageing, disease, disuse or exercise, by removing existing and adding new bone tissue. It has been recognised that osteocytes are the key cells which orchestrate bone adaptation (Tatsumi et al., 2007). Osteocytes are ovoid cells approximately 10 µm long, surrounded by a pericellular matrix (PCM). The osteocytes and their processes form the osteocyte network (ON), which is housed within the lacuno-canalicular network (LCN), a system of voids and channels in the calcified bone matrix (Fig. 1). Neve et al., 2012). Knowledge of the three-dimensional (3D) structure of the ON&LCN would inform conclusions about the function and malfunction of osteocytes for different bone states in development, ageing, disease, disuse or exercise. More specifically, enhanced knowledge would improve the predictive power and accuracy of computational models, which attempt to elucidate the mechanisms of mechanotransduction using 3D geometries for the ON&LCN. Recent finite element and fluid-structure interaction models have used relatively low resolution image data and made a priori assumptions about the ...

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Discordant growth of nasal cartilage and bone contributes to phenotypic variability of the skull in a mouse model

Book

Moore

Tourigny

et al. 2023

Developmental Dynamics

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Background: We previously determined a nonlinear relationship between connexin 43 (Cx43) function and craniofacial phenotypic variation in the mutant mouse model G60S/+, and that this variation was driven by nasal bone deviation. While nonlinearities in the genotype-phenotype map appear to be common, few studies have looked at the developmental processes that underlie this nonlinearity. Here, we investigated the potential tissue-level developmental determinants of the variation in nasal bone phenotype in G60S/+ mice through postnatal development.Results: The deviated nasal bone phenotype arises by postnatal day 21 and becomes more severe by 3 months in G60S/+ mice. Measures of nasal bone remodeling including the number of osteoclasts, mineralizing surface, mineral apposition rate, and bone formation rate are significantly greater in G60S/+ mice compared to wild-type mice at 2 months, but these differences do not correspond with nasal bone deviation. The degree of nasal bone deviation does significantly and negatively correlate with the ratio between nasal bone and cartilaginous nasal septum length. Conclusions: Our findings indicate that the mean phenotypic changes observed between G60S/+ and wild-type mice are due to reduced bone growth, but the increased phenotypic variation found within mutant mice is due to discordant growth between nasal cartilage and bone. K E Y W O R D S bone remodeling, connexin 43, osteoblasts, osteoclasts, postnatal growth 1 | INTRODUCTION To understand the mechanistic basis of both typical and aberrant morphogenesis, we require a well-developed genotype-to-phenotype map. For structures that are Shae A. Book and Alyssa C. Moore are co-first authors.

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Connexin 43 Channels Are Essential for Normal Bone Structure and Osteocyte Viability

Cited by 96 publications

References 44 publications

Defective signaling, osteoblastogenesis and bone remodeling in a mouse model of connexin 43 C-terminal truncation

Defective signaling, osteoblastogenesis and bone remodeling in a mouse model of connexin 43 C-terminal truncation

High-resolution 3D imaging of osteocytes and computational modelling in mechanobiology: insights on bone development, ageing, health and disease

Discordant growth of nasal cartilage and bone contributes to phenotypic variability of the skull in a mouse model

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