Pannexins in the musculoskeletal system: new targets for development and disease progression

Abstract

During cell differentiation, growth, and development, cells can respond to extracellular stimuli through communication channels. Pannexin (Panx) family and connexin (Cx) family are two important types of channel-forming proteins. Panx family contains three members (Panx1-3) and is expressed widely in bone, cartilage and muscle. Although there is no sequence homology between Panx family and Cx family, they exhibit similar configurations and functions. Similar to Cxs, the key roles of Panxs in the maintenance of physiological functions of the musculoskeletal system and disease progression were gradually revealed later. Here, we seek to elucidate the structure of Panxs and their roles in regulating processes such as osteogenesis, chondrogenesis, and muscle growth. We also focus on the comparison between Cx and Panx. As a new key target, Panxs expression imbalance and dysfunction in muscle and the therapeutic potentials of Panxs in joint diseases are also discussed.

Fig. 1

Structure of GJ proteins. a Prototypic secondary structure of GJ proteins (Panxs and Cxs). Each Panx and Cx monomer consists of 2 extracellular loops, 4 transmembrane domains, and 1 intracellular loop. b GJ and hemichannels assembled by Panxs and Cxs subunits. Panx subunit function as channels, termed HCs (heptamer), which allow the exchange of small molecules and ions. Cx HCs (hexamer) are similar. What is currently certain is that two Cx HCs can combine to form GJs, but whether Panx HCs can form GJs is still questionable. c Schematic diagram of Panxs positioning and channel functions. Panxs can aggregate to form single-membrane channels, which are located on the cell surface and ER and are responsible for the intracellular and extracellular exchange of metabolites and ions such as ATP and Ca²⁺ and the release of Ca²⁺ in the ER (not include Panx1). (ER endoplasmic reticulum, ATP adenosine triphosphate, cAMP cyclic adenosine monophosphate, GJ gap junction, HCs hemichannels.)

Fig. 2

Structure of Panxs and Cxs formed hemichannels. In this pattern diagram, since the respective structures of Panxs and Cxs are similar, we use the structural diagrams of Cx43 and Panx1 as representatives for display

Fig. 3

Panx participates in signaling pathways in osteoblast differentiation. Panx3 HCs release intracellular ATP into the extracellular space, where ATP subsequently binds to P2 receptor in an autocrine or paracrine manner. The combination of ATP and P2 receptor activates PI3K/Akt signaling, which in turn activates the Panx3 ER Ca²⁺ channel to release Ca²⁺. Upon Ca²⁺ binding, CaM activates the CN signaling pathway. CN-mediated dephosphorylation activates the NFATc1 in T cells. Activated NFATc1 subsequently translocates into the nucleus and promotes Osx, ALP and OCN. P2 receptor can also activate the Akt/MDM2 pathway through PI3K to promote the degradation of the osteoblast differentiation inhibitor p53. In addition, intracellular Ca²⁺ spreads to neighboring cells through Panx to promote osteoblast differentiation. (HCs hemichannels, ATP adenosine triphosphate, PI3K phosphatidylinositol 3-kinase, ER endoplasmic reticulum, CaM calmodulin, CN phosphatase calcineurin, NFATc1 nuclear factor of activated T cell calcineurin independent 1, ALP alkaline phosphatase, MDM2 mouse double minute 2 homolog, Osx Osterix, OCN osteocalcin, NFAT nuclear factor of activated T cells.)

Fig. 4

Panx is involved in the signaling pathways of osteoprogenitor cell proliferation and differentiation. Panx HCs release intracellular ATP, which inhibits PKA/CREB signaling and reduces intracellular cAMP content. Inactivation of PKA activates GSK3β, leading to degradation of β-catenin. Wnt/β-catenin signaling is subsequently inhibited and CREB activity is also reduced, thereby inhibiting cell proliferation. In addition, extracellular ATP activates PI3K/Akt signaling, stimulating the opening of Panx3 ER Ca²⁺ channels, thereby activating CaM/CaMK signaling, leading to the activation of Smad and cell cycle inhibitor p21, thereby promoting cell cycle exit. (HCs hemichannels, PKA protein kinase A, cAMP cyclic adenosine monophosphate, CREB cAMP response element binding, GSK3β glycogen synthase kinase 3β, PI3K phosphatidylinositol 3-kinase, ER endoplasmic reticulum, CaM calmodulin, CaMK calmodulin kinase, APC adenomatous polyposis coli, LRP5/6 low-density lipoprotein receptor-related proteins 5 and 6, TCF T cell factor, ATP adenosine triphosphate.)

Fig. 5

Panxs regulate chondrogenesis, osteogenesis, and myoblast proliferation and differentiation. (Osx Osterix, BMP2 Bone morphogenetic protein 2, NFATc1 Nuclear factor of calcineurin-dependent 1.)

Fig. 6

The role of Pannexin channels in healthy and arthritic joints. In healthy cartilage, chondrocytes mediate ATP release through Panx3, and then intracellular ATP reduction activates phosphokinase A and CREB phosphorylation. In arthritic diseases, Panx3 activates P2 receptors through Runx2-mediated ATP release in chondrocytes. Replicate cascades leading to ERK1/2 and MMP13-mediated signaling. Abnormal differentiation of chondrocytes into a hypertrophic chondrocyte phenotype ultimately leads to arthritis. (ALP alkaline phosphatase, cAMP cyclic adenosine monophosphate, CREB cAMP response element binding, MMP13 matrix metalloproteinase 13, ERK1/2 extracellular signal-regulated kinase 1/2, PKA protein kinase A, RUNX2 Runt-related transcription factor 2.)