Age- and sex-dependent role of osteocytic pannexin1 on bone and muscle mass and strength

Alexandra Aguilar-Perez,Joseph E Rupert,Julian E Dilley,Roger J Thompson,Rafael Pacheco-Costa,Padmini Deosthale,Teresa A Zimmers,Matthew R Allen,Alyson L Essex,Leland Gomez,Lilian I Plotkin,Hannah M Davis,Emily G Atkinson

doi:10.1038/s41598-019-50444-1

Abstract

Pannexins (Panxs), glycoproteins that oligomerize to form hemichannels on the cell membrane, are topologically similar to connexins, but do not form cell-to-cell gap junction channels. There are 3 members of the family, 1–3, with Panx1 being the most abundant. All Panxs are expressed in bone, but their role in bone cell biology is not completely understood. We now report that osteocytic Panx1 deletion (Panx1Δot) alters bone mass and strength in female mice. Bone mineral density after reaching skeletal maturity is higher in female Panx1Δot mice than in control Panx1fl/fl mice. Further, osteocytic Panx1 deletion partially prevented aging effects on cortical bone structure and mechanical properties. Young 4-month-old female Panx1Δot mice exhibited increased lean body mass, even though pannexin levels in skeletal muscle were not affected; whereas no difference in lean body mass was detected in male mice. Furthermore, female Panx1-deficient mice exhibited increased muscle mass without changes in strength, whereas Panx1Δot males showed unchanged muscle mass and decreased in vivo maximum plantarflexion torque, indicating reduced muscle strength. Our results suggest that osteocytic Panx1 deletion increases bone mass in young and old female mice and muscle mass in young female mice, but has deleterious effects on muscle strength only in males.

Highlights

Pannexin 1 (Panx1) is the most widespread member of the pannexin family of proteins and its mRNA expression has been detected in all bone cells[1,2,3]
More recently we have reported that apoptotic osteocytic cells release factors to the culture media in vitro that stimulate osteoclastogenesis; and that prevention of osteocytic cell apoptosis reversed the increase in osteoclast formation induced by the conditioned media from osteocytic cells[13]
We found that Panx[1] deletion has small but significant effects on bone mass that is more evident as the mice age

Summary

Introduction

Pannexin 1 (Panx1) is the most widespread member of the pannexin family of proteins and its mRNA expression has been detected in all bone cells[1,2,3]. Activation of caspase-3 in apoptotic cells results in cleavage of the Panx[1] auto-inhibitory C-terminus tail, irreversibly opening the channels[8] He increase in selective membrane permeability that occurs in the early stages of apoptosis has been ascribed to Panx[1] channel opening. Treating these bones with an apoptosis inhibitor reduced both apoptosis and osteoclast-inducing activity[14] Taken together, these pieces of evidence suggest that osteocyte apoptosis leads to the release of osteoclastogenic factors. These pieces of evidence suggest that osteocyte apoptosis leads to the release of osteoclastogenic factors This led us to propose that, with aging and increased osteocyte apoptosis, Panx[1] channels open and release factors that increase osteoclastogenesis and bone resorption. Our results suggest that osteocytic Panx[1] can mediate the effect of osteocytes as regulators of bone and muscle mass in an age- and sex-dependent manner

Methods

Results

Conclusion