Pannexin 3 and connexin 43 modulate skeletal development through their distinct functions and expression patterns

Abstract

Pannexin 3 (Panx3) and connexin 43 (Cx43; also known as GJA1) are two major gap junction proteins expressed in osteoblasts. Here, we studied their functional relationships in skeletal formation by generating showed no obvious abnormalities, except for less mineralization of the skull. In Panx3 −/− mice, proliferation of chondrocytes and osteoblasts increased and differentiation of these cells was inhibited. Panx3 promoted expression of osteogenic proteins such as ALP and Ocn (also known as ALPL and BGLAP, respectively), as well as Cx43, by regulating Osx (also known as SP7) expression. Panx3 was induced in the early differentiation stage and reduced during the maturation stage of osteoblasts, when Cx43 expression increased in order to promote mineralization. Furthermore, only Panx3 functioned as an endoplasmic reticulum (ER) Ca 2+ channel to promote differentiation, and it could rescue mineralization defects in Cx43 −/− calvarial cells. Our findings reveal that Panx3 and Cx43 have distinct functions in skeletal formation.

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

“…However, organ-, cell-, or time-specific expression of gap junction proteins are suggesting that each of gap junction proteins have specific roles and functions. In fact, connexin 43 (Cx43) plays important roles in osteoblast function and differentiation, but Panx3 deficient mice show more severe skeletal phenotype than Cx43 deficient mice [19]. This is due to the difference of channel properties between Panxs and connexins.…”

“…The ER plays a predominant role in Ca 2+ storage and regulates intracellular Ca 2+ levels in many cellular processes, including osteoblast differentiation. In osteoblasts, Panx3 functions as the ER Ca 2+ channel that activates CaMKII-Smad signaling and Osx expression [15, 19]. Tooth development is mediated by various growth factors.…”

“…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.…”

Gap junction gene and protein families: Connexins, innexins, and pannexins

“…The only human gene mutation reported to date encodes a non-functional PANX1 variant that does not inhibit the function of wild type PANX1; it was found in a patient (homozygous for this allele) with disorders in several organs [49]. Investigations of pannexin-null mice have also implicated pannexins in contributing to protection from ischemic stroke injury [4,21], modulation of neuronal excitability and learning [43,44], bone development [27], narcotic withdrawal [14], and sleep-wake cycle regulation and behavior [29]. …”

The Role of Signaling Pathway on Osteoprogenitor Cell Behavior and Bone Formation

“…Panx1 and 2 are ubiquitously expressed with particularly strong expression in the central nervous system (52). Panx3 is a member that was most recently identified by genome bioinformatic analysis (53). However, Panx 3 is expressed in certain soft tissues, such as skin and coronary arteries and developing hard tissues, including cartilage and bone.…”