Pannexin 3 is required for normal progression of skeletal development in vertebrates

Oh, Se‐Kyung; Shin, Jeong-Oh; Baek, Jeong‐In; Lee, Jinwook; Bae, Jae Woong; Ankamerddy, Harinarayana; Kim, Myoung-Jin; Huh, Tae‐Lin; Ryoo, Zae-Young; Kim, Un-Kyung; Bok, Jinwoong; Lee, Kyu-Yup

doi:10.1096/fj.15-273722

Cited by 26 publications

(46 citation statements)

References 38 publications

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“…(), which includes many of the authors of the present study, and that of Oh et al. (). Our initial study using a global Panx3‐null mouse was focused on the role of Panx3 in the onset of osteoarthritis (Moon et al.…”

Section: Discussionmentioning

confidence: 85%

“…Oh et al. () used a different global Panx3‐null mouse to study the effects of Panx3 on skeletal development, as compared with previously published in vitro studies (i.e. Iwamoto et al.…”

Section: Discussionmentioning

confidence: 99%

“…; Oh et al. ). Panx3 expression also promotes the differentiation of chondrocytes from a proliferative to post‐mitotic state (Iwamoto et al.…”

Section: Introductionmentioning

confidence: 97%

“…The second paper by Oh et al. () used a different global Panx3‐null mouse as well as Panx3 knockdown morpholinos in zebrafish to study the effects of Panx3 in bone development. This latter study supports the premise that Panx3 plays a key role in chondrocyte and osteoblast proliferation and differentiation.…”

Section: Introductionmentioning

confidence: 99%

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Global deletion of Panx3 produces multiple phenotypic effects in mouse humeri and femora

et al. 2016

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Pannexins form single-membrane channels that allow passage of small molecules between the intracellular and extracellular compartments. Of the three pannexin family members, Pannexin3 (Panx3) is the least studied but is highly expressed in skeletal tissues and is thought to play a role in the regulation of chondrocyte and osteoblast proliferation and differentiation. The purpose of our study is to closely examine the in vivo effects of Panx3 ablation on long bone morphology using micro-computed tomography. Using Panx3 knockout (KO) and wildtype (WT) adult mice, we measured and compared aspects of phenotypic shape, bone mineral density (BMD), cross-sectional geometric properties of right femora and humeri, and lean mass. We found that KO mice have absolutely and relatively shorter diaphyseal shafts compared with WT mice, and relatively larger areas of muscle attachment sites. No differences in BMD or lean mass were found between WT and KO mice. Interestingly, KO mice had more robust femora and humeri compared with WT mice when assessed in cross-section at the midshaft. Our results clearly show that Panx3 ablation produces phenotypic effects in mouse femora and humeri, and support the premise that Panx3 has a role in regulating long bone growth and development.

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Section: Discussionmentioning

confidence: 85%

“…Oh et al. () used a different global Panx3‐null mouse to study the effects of Panx3 on skeletal development, as compared with previously published in vitro studies (i.e. Iwamoto et al.…”

Section: Discussionmentioning

confidence: 99%

“…; Oh et al. ). Panx3 expression also promotes the differentiation of chondrocytes from a proliferative to post‐mitotic state (Iwamoto et al.…”

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Global deletion of Panx3 produces multiple phenotypic effects in mouse humeri and femora

et al. 2016

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“…In addition, Panx3 is induced by Bone morphogenetic protein 2 (BMP2) and a target gene of Runt-related transcription factor 2 (Runx2), which is a key transcription factor for bone formation [17]. Panx3 knockout mice evidently demonstrated that Panx3 is essential for normal skeletal development [18, 19]. Thus, Panx3 plays a crucial role in hard tissue development.…”

Section: Introductionmentioning

confidence: 99%

Pannexin 3 regulates proliferation and differentiation of odontoblasts via its hemichannel activities

et al. 2017

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Highly coordinated regulation of cell proliferation and differentiation contributes to the formation of functionally shaped and sized teeth; however, the mechanism underlying the switch from cell cycle exit to cell differentiation during odontogenesis is poorly understood. Recently, we identified pannexin 3 (Panx3) as a member of the pannexin gap junction protein family from tooth germs. The expression of Panx3 was predominately localized in preodontoblasts that arise from dental papilla cells and can differentiate into dentin-secreting odontoblasts. Panx3 also co-localized with p21, a cyclin-dependent kinase inhibitor protein, in preodontoblasts. Panx3 was expressed in primary dental mesenchymal cells and in the mDP dental mesenchymal cell line. Both Panx3 and p21 were induced during the differentiation of mDP cells. Overexpression of Panx3 in mDP cells reduced cell proliferation via up-regulation of p21, but not of p27, and promoted the Bone morphogenetic protein 2 (BMP2)-induced phosphorylation of Smad1/5/8 and the expression of dentin sialophosphoprotein (Dspp), a marker of differentiated odontoblasts. Furthermore, Panx3 released intracellular ATP into the extracellular space through its hemichannel and induced the phosphorylation of AMP-activated protein kinase (AMPK). 5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR), an activator of AMPK, reduced mDP cell proliferation and induced p21 expression. Conversely, knockdown of endogenous Panx3 by siRNA inhibited AMPK phosphorylation, p21 expression, and the phosphorylation of Smad1/5/8 even in the presence of BMP2. Taken together, our results suggest that Panx3 modulates intracellular ATP levels, resulting in the inhibition of odontoblast proliferation through the AMPK/p21 signaling pathway and promotion of cell differentiation by the BMP/Smad signaling pathway.

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Global Deletion of Pannexin 3 Resulting in Accelerated Development of Aging‐Induced Osteoarthritis in Mice

Moon

Shao

Wambiekele

et al. 2021

Arthritis & Rheumatology

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Objective Osteoarthritis (OA) results in pathologic changes in the joint tissue. The mechanisms driving disease progression remain largely unclear, and thus disease‐modifying treatments are lacking. Pannexin 3 (Panx3) was identified as a potential mediator of cartilage degeneration in OA, and our previous study in mice indicated that deletion of the Panx3 gene delayed surgically induced cartilage degeneration. This study was undertaken to examine the role of Panx3 in other OA subtypes, particularly primary OA during aging, in a mouse model of aging‐induced OA. Methods Wild‐type (WT) and Panx3−/− C57BL/6J (Black‐6) mice, ages 18–24 months, were analyzed by micro–computed tomography to investigate bone mineral density and body composition. Joints were harvested from the mice, and histopathologic analysis of the joint tissue for OA development was conducted with a specific focus on changes in articular cartilage, subchondral bone, and synovial tissue. Results Global loss of Panx3 in aging mice was not associated with increased mortality or changes in body composition. Mice lacking Panx3 had shorter appendicular skeletons than WT mice, but overall the body compositions appeared quite similar. Panx3 deletion dramatically accelerated cartilage degeneration and subchondral bone thickening with aging in both 18‐month‐old and 24‐month‐old mice, while promoting synovitis in 18‐month‐old mice. Conclusion These observations in a mouse model of OA suggest that Panx3 has a protective role against the development of primary aging‐associated OA. It appears that Panx3 has opposing context‐specific roles in joint health following traumatic injury versus that associated with aging. These data strongly suggest that there are differences in the molecular pathways driving different subtypes of OA, and therefore a detailed understanding of these pathways could directly improve strategies for OA diagnosis, therapy, and research.

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Pannexin 3 is required for normal progression of skeletal development in vertebrates

Cited by 26 publications

References 38 publications

Global deletion of Panx3 produces multiple phenotypic effects in mouse humeri and femora

Global deletion of Panx3 produces multiple phenotypic effects in mouse humeri and femora

Pannexin 3 regulates proliferation and differentiation of odontoblasts via its hemichannel activities

Global Deletion of Pannexin 3 Resulting in Accelerated Development of Aging‐Induced Osteoarthritis in Mice

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