Yoda1 Restored the Response of Aged Mouse Bone to Mechanical Loading
Yoda1 Restored the Response of Aged Mouse Bone to Mechanical Loading
On 21 August, Aging Cell published a study of experiments in 19-month-old mice. Yoda1, combined with two weeks of cyclic tibial compression, induced new tissue formation in the outer layer of the bone. The effect disappeared when the researchers blocked two components of signal transduction within bone cells.
Bone responds to regular mechanical loading by adding tissue to the cortical layer, its dense outer shell. Osteocytes, the cells embedded within this tissue, are the first to detect deformation. In 16-week-old mice, two weeks of cyclic tibial compression increased cortical bone formation. In 19-month-old animals, the same protocol no longer changed the main measures of cortical bone structure.
In a previous study by the same group, direct activation of connexin 43 hemichannels in aged bone restored its response to mechanical loading. Connexin 43 is a protein that forms pores in the osteocyte membrane through which small signaling molecules can pass. The new study examined the upstream component of this process. The authors selected Piezo1, a deformation-sensitive ion channel in the osteocyte membrane. Yoda1 lowers the deformation threshold at which this channel opens, as shown by a structural study of Piezo1.
In the new experiment, 19-month-old male mice received Yoda1 one hour before compression. The main series included six mice, and the unloaded bone in the other leg served as a paired control. Neither Yoda1 nor mechanical loading alone changed the main measures of cortical bone structure. Their combination reduced the bone marrow cavity and increased cortical area and thickness.
The authors then examined how the mechanical signal led to tissue formation. In a cellular model of osteocyte aging, fluid flow combined with Yoda1 increased the proximity of Piezo1 to connexin 43 and promoted connexin 43 hemichannel opening. The PI3K-Akt signaling pathway supported hemichannel opening, allowing the cells to release more prostaglandin E2, a signaling molecule. At the same time, the level of sclerostin, a protein that inhibits bone formation, decreased.
Gap19, a peptide that blocks connexin 43 hemichannels, prevented prostaglandin E2 release, the reduction in sclerostin, and the compression-induced changes in bone structure. The PI3K inhibitor LY294002 also prevented hemichannel opening and cortical bone formation. Yoda1 lowered the threshold for Piezo1 opening, while deformation initiated a signaling sequence confirmed by the inhibitor experiments. The osteocyte signal ultimately led to the formation of new bone tissue.