Osteocytes, the stellate shape, dendritic appearing cells, are the most abundant cells in the mature bone tissue. Osteocyte cell bodies and their dendritic processes reside in void spaces called lacunae and canaliculi, respectively, which together comprise the lacunar-canalicular space (LCS) of bone. The LCS contains a fluid layer between the cell and the bony wall and that fluid layer governs osteocyte’s numerous functions. These include orchestrating bone remodeling, regulating mineral systemically and locally and sensing mechanical loads. Furthermore, the LCS is not static. Small amounts of bone can be removed by osteocytes from their lacunar walls through the process of “osteocytic osteolysis”. This process occurs with a wide range of physiological challenges, including microgravity, PTH administration and lactation, but its significance to bone’s mechanical function is not understood.

It is well established that vascular porosity strongly and inversely influences bone stiffness and strength. Changing vascular void volume occurs through osteoclasts and bone remodeling, which operates over a time scale on the order of months. In our first studies, we tested whether changes in LCS void volume due to osteocytic osteolysis, which operates over a time period of days to weeks, is sufficient to modulate bone mechanical properties. We used a mouse lactation model to induce osteocytic osteolysis that can also recover when lactation ceases. Cortical bone tissue-level mechanical properties were measured using microindentation. We examined changes in LCS dimensions and surrounding bone composition using a novel super-resolution microscopy approach, high-resolution back-scattered scanning electron microscopy and Raman microspectroscopy. Lactation caused a marked reduction (~15%) in bone tissue level mechanical properties and this reduction recovered completely by 1-week post-lactation. Mineralization or chemical composition in bone were unchanged. Thus, alterations in mechanical properties caused by lactation were due to osteocytic osteolysis. i.e., changes in LCS void space.

There is an emerging problem of bone fractures among patients with long-term pharmacological proton pump inhibitor (PPI) use and the underlying mechanism is still unknown. In the second series of studies, we used a PPI (Omeprazole) to test whether long-term treatment of PPI influence bone material properties. We discovered that long-term PPI altered bone tissue level material properties independent of whole bone mechanical properties and these changes in tissue properties were associated with reductions in LCS void space. Furthermore, we used omeprazole to test whether removal of mineral from the LCS surface during osteocytic osteolysis depends on acidification. The reduced bone material properties caused by osteocytic osteolysis were prevented with PPI administration. This rapid effect of PPI is intriguing and such changes can adversely affect bone fragility.

These findings demonstrate for the first time that bone tissue-level material properties are rapidly and reversibly modulated by osteocytes in response to physiological challenges. Furthermore, these data reveal a previously unknown mechanism by which bone can quickly and dynamically adjust its material properties to meet mechanical demands.