Osteocytic Connexin43 Channels Regulate Bone–Muscle Crosstalk

Abstract

Bone–muscle crosstalk plays an important role in skeletal biomechanical function, the progression of numerous pathological conditions, and the modulation of local and distant cellular environments. Previous work has revealed that the deletion of connexin (Cx) 43 in osteoblasts, and consequently, osteocytes, indirectly compromises skeletal muscle formation and function. However, the respective roles of Cx43-formed gap junction channels (GJs) and hemichannels (HCs) in the bone–muscle crosstalk are poorly understood. To this end, we used two Cx43 osteocyte-specific transgenic mouse models expressing dominant negative mutants, Δ130–136 (GJs and HCs functions are inhibited), and R76W (only GJs function is blocked), to determine the effect of these two types of Cx43 channels on neighboring skeletal muscle. Blockage of osteocyte Cx43 GJs and HCs in Δ130–136 mice decreased fast-twitch muscle mass with reduced muscle protein synthesis and increased muscle protein degradation. Both R76W and Δ130–136 mice exhibited decreased muscle contractile force accompanied by a fast-to-slow fiber transition in typically fast-twitch muscles. In vitro results further showed that myotube formation of C2C12 myoblasts was inhibited after treatment with the primary osteocyte conditioned media (PO CM) from R76W and Δ130–136 mice. Additionally, prostaglandin E2 (PGE2) level was significantly reduced in both the circulation and PO CM of the transgenic mice. Interestingly, the injection of PGE2 to the transgenic mice rescued fast-twitch muscle mass and function; however, this had little effect on protein synthesis and degradation. These findings indicate a channel-specific response: inhibition of osteocytic Cx43 HCs decreases fast-twitch skeletal muscle mass alongside reduced protein synthesis and increased protein degradation. In contrast, blockage of Cx43 GJs results in decreased fast-twitch skeletal muscle contractile force and myogenesis, with PGE2 partially accounting for the measured differences.

Effect of High Static Magnetic Fields on Biological Activities and Iron Metabolism in MLO-Y4 Osteocyte-like Cells

“…Moreover, osteocytes abundantly express Cx43 proteins, which form both gap junctions and hemichannels. Cx43 gap junctions can facilitate the passage of small signaling molecules between coupled cells, whereas Cx43 hemichannels can mediate communication between the cell and the extracellular environment [ 34 ]. Herein, we found that HiSMF can promote the expression of Cx43 protein in osteocytes.…”

Iron Oxide Nanoparticles Combined with Static Magnetic Fields in Bone Remodeling

“…Osteocytes, the most abundant cells in bone tissue, are descended from mature, matrix-producing osteoblasts and play a key role in regulating bone remodeling [ 61 ]. However, there are few studies on the effects of SMFs on osteocytes.…”

Connexin 43 Channels in Osteocytes Are Necessary for Bone Mass and Skeletal Muscle Function in Aged Male Mice

“…Osteocytes, as endocrine cells, also play an important role in bone-muscle crosstalk [ 1 , 5 , 40 ]. The findings in our recent study indicate that impairment of Cx43-based HCs and GJs in osteocytes respectively decreases fast-twitch muscle mass and muscle contractile force in young mice [ 41 ]. In this study, however, except for the decrease of slow-twitch muscle contractile force in old Δ130–136 mice, we did not observe additional changes in muscle mass or myofiber size.…”