Pannexin 3 deletion reduces fat accumulation and inflammation in a sex-specific manner

Wakefield, C. Brent; Lee, Vanessa R.; Johnston, Danielle; Boroumand, Parastoo; Pillon, Nicolas; Sayedyahossein, Samar; O'Donnell, Brooke L; Tang, Justin; Sanchez-Pupo, Rafael E; Barr, Kevin; Gros, Robert; Flynn, Lauren E.; Borradaile, Nica M.; Klip, Amira; Beier, Frank; Peñuela, Silvia

doi:10.1038/s41366-021-01037-4

Cited by 10 publications

(23 citation statements)

References 49 publications

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“…In healthy, unchallenged dorsal skin, we found that PANX3 seems to play more of an anti-inflammatory role evidenced by its ablation increasing inflammatory signaling. Using the same KO mouse model we previously showed that Panx3 deletion reduced the inflammatory index in male visceral fat (Wakefield et al, 2021). Despite these differences, the contrary findings may not result from tissue dependence of PANX3 function, but rather age differences since visceral fat findings were in 30-week-old mice, whereas dermatitis cases were documented in 10.5-18-month-old mice.…”

Section: Discussionmentioning

confidence: 90%

“…Phenotypically, both Panx1 and Panx3 KO models exhibit a reduction in the epidermal and dermal area, but unlike Panx1 KO mice which exhibit increased subcutaneous fat, the hypodermal area is significantly reduced in the Panx3 KO mice (Penuela et al, 2014). We previously found that the reduction in hypodermal area in the Panx3 KO was due to reduced adipocyte cell number rather cell size (Wakefield et al, 2021). PANX2 isoform 202 was downregulated in Panx3 KO dorsal skin compared to controls which is, to our knowledge, the first report of a reduction in pannexin levels when another family member is ablated.…”

Section: Discussionmentioning

confidence: 99%

“…Using the punch biopsy model, Zhang et al (2019) found that at the wound site, β-catenin mRNA was significantly reduced in KO wounded skin compared to controls. Recently, we discovered that PANX1 binds directly to β-catenin, a main player in the Wnt pathway, for signaling purposes most likely independent of PANX1 channel function (Sayedyahossein et al, 2021). Thus, it is possible PANX3 may also act as a scaffold protein to βcatenin or other Wnt signaling components, functioning through its interactome rather than as a channel.…”

Section: Discussionmentioning

confidence: 99%

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Pannexin 3 channels regulate architecture, adhesion, barrier function and inflammation in the skin

O'Donnell

Sanchez-Pupo

Sayedyahossein

et al. 2022

Preprint

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The channel-forming glycoprotein Pannexin 3 (PANX3) functions in cutaneous wound healing and keratinocyte differentiation, but its role in skin homeostasis through aging is not yet understood. We found that PANX3 is absent in newborn skin but becomes upregulated with age. We characterized the skin of global Panx3 knockout mice (KO) and found that KO dorsal skin showed sex-differences at different ages, but generally had reduced dermal and hypodermal areas compared to aged-matched controls. Transcriptomic analysis of KO epidermis revealed reduced E-cadherin stabilization and Wnt signalling compared to WT, consistent with the inability of primary KO keratinocytes to adhere in culture, and diminished epidermal barrier function in KO mice. We also observed increased inflammatory signalling in KO epidermis and higher incidence of dermatitis in aged KO mice compared to wildtype controls. These findings suggest that during skin aging, PANX3 is critical in the maintenance of dorsal skin architecture, keratinocyte cell-cell and cell-matrix adhesion and inflammatory skin responses.SummaryPannexin 3 is a new regulator of skin structure and function. Here, O’Donnell et al. demonstrate its role in the maintenance of proper skin architecture with aging, epidermal barrier function, inflammation, and keratinocyte adhesion through Wnt signalling and E-cadherin stabilization.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Pannexin 3 channels regulate architecture, adhesion, barrier function and inflammation in the skin

O'Donnell

Sanchez-Pupo

Sayedyahossein

et al. 2022

Preprint

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“…Mice ate regular chow ad libitum. Mice were weighed bi-weekly and body composition was assessed at 24 and 30 weeks of age, which was published previously [15]. WT and Panx3 KO mice were congenic.…”

Section: Methodsmentioning

confidence: 99%

Pannexin 3deletion in mice results in knee osteoarthritis and intervertebral disc degeneration after forced treadmill running

Wakefield

Hutchinson

Tang

et al. 2023

Preprint

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Pannexin 3 (Panx3) is a glycoprotein that forms mechanosensitive channels expressed in chondrocytes and annulus fibrosus cells of the intervertebral disc (IVD). Evidence suggests Panx3 plays contrasting roles in traumatic versus aging osteoarthritis (OA) and intervertebral disc degeneration (IDD). However, whether its deletion influences the response of joint tissue to mechanical stress is unknown. The purpose of this study was to determine if Panx3 deletion in mice causes increased knee joint OA and IDD after forced treadmill running. Male and female wildtype (WT) and Panx3 knockout (KO) mice were randomized to either a no exercise group (sedentary; SED) or daily forced treadmill running (forced exercise; FEX) from 24 to 30 weeks of age. Knee cartilage, tibial subchondral bone and IVD histopathology were evaluated by histology. Both male and female Panx3 KO mice developed larger superficial defects of the tibial cartilage after forced treadmill running compared to SED WT mice. Additionally, both male and female Panx3 KO mice developed a sclerotic secondary ossification center of the tibia with running. In the lower lumbar spine, both male and female Panx3 KO mice developed histopathological features of IDD after running compared to SED WT mice. Clinical Significance: These findings suggest that the combination of deleting Panx3 and forced treadmill running induces OA and causes histopathological changes associated with degeneration of the IVDs in mice.

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“…Pannexins are involved in vital cellular signalling processes such as membrane purinergic signalling through ATP release and intracellular Ca 2+ release from the endoplasmic reticulum [9]. They have been implicated in a breadth of physiological and pathological processes including cell death [10][11][12][13][14], osteoarthritis [7,15], bone formation [6,16], blood pressure regulation [17][18][19], inflammation [4,10,11,17,[20][21][22][23][24], fat accumulation [4,25], wound healing [26] and are dysregulated in many cancers [27]. Thus, pannexins are hypothesized to be a promising therapeutic target for a variety of diseases.…”

Section: Introductionmentioning

confidence: 99%

Potential Implications of Exercise Training on Pannexin Expression and Function

Wakefield¹,

Peñuela²

2022

J Vasc Res

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Pannexins (PANX1, 2, 3) are channel-forming glycoproteins that are expressed throughout the cardiovascular and musculoskeletal system. The canonical function of these proteins is to release nucleotides that act as purinergic signalling at the cell membrane or Ca<sup>2+</sup> channels at the endoplasmic reticulum membrane. These two forms of signalling are essential for autocrine and paracrine signalling in health, and alterations in this signalling have been implicated in the pathogenesis of many diseases. Many musculoskeletal and cardiovascular diseases are largely the result of a lack of physical activity which causes altered gene expression. Considering exercise training has been shown to alter a wide array of gene expression in musculoskeletal tissues, understanding the interaction between exercise training, gene function and expression in relevant diseases is warranted. With regards to pannexins, multiple publications have shown that exercise training can influence pannexin expression and may influence the significance of its function in certain diseases. This review further discusses the potential interaction between exercise training and pannexin biology in relevant tissues and disease models. We propose that exercise training in relevant animal and human models will provide a more comprehensive understanding of the implications of pannexin biology in disease.

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Pannexin 3 deletion reduces fat accumulation and inflammation in a sex-specific manner

Cited by 10 publications

References 49 publications

Pannexin 3 channels regulate architecture, adhesion, barrier function and inflammation in the skin

Pannexin 3 channels regulate architecture, adhesion, barrier function and inflammation in the skin

Pannexin 3deletion in mice results in knee osteoarthritis and intervertebral disc degeneration after forced treadmill running

Potential Implications of Exercise Training on Pannexin Expression and Function

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