Osteocytes (resident bone cells) are believed to sense loading-induced interstitial fluid flow in bone and transduce the signals to osteoclasts (bone resorption cells) and osteoblasts (bone formation cells) to regulate bone remodeling. Recent studies have shown that bone disuse causes osteocyte apoptosis, which precedes osteoclast activity at the local remodeling site. Although osteoclast precursors are known to travel via the circulation, the specific mechanism by which they are transported to the remodeling site is unclear.

We hypothesized that lack of fluid flow induces osteocyte apoptosis. Furthermore, we hypothesized that osteocyte populations containing apoptotic osteocytes secrete cytokines that:​ 1) promote angiogenesis, and 2) activate the endothelium to promote osteoclast precursor adhesion to the endothelium such that osteoclast precursors can be delivered closer and directly to the remodeling site.

In our in vitro studies, we found that lack of oscillatory fluid flow (mimicking mechanical disuse) promotes osteocyte apoptosis. In addition, osteocyte populations containing apoptotic cells promote endothelial cell proliferation, migration, and tubule formation. Inhibition of the potent angiogenic cytokine, vascular endothelial growth factor (VEGF), abrogated osteocyte apoptosis-mediated angiogenesis.

Furthermore, we found that osteocyte populations containing apoptotic cells secrete cytokines that promoted osteoclast precursor adhesion. Upon further investigation, we found that apoptotic osteocytes secreted elevated levels of inflammatory cytokine interleukin 6 (IL-6), and its soluble receptor, sIL-6R. We demonstrated that both IL-6 and sIL-6R are required to activate the endothelium to express ICAM-1. Inhibition of ICAM-1 and IL-6 by blocking antibodies abolished apoptotic osteocyte-mediated osteoclast precursor adhesion.

Our findings suggest for the first time that osteocytes communicate to endothelial cells directly to mediate angiogenesis and osteoclast precursor adhesion. Results from this study may assist in a better understanding of osteoclast precursor recruitment at the initial onset of bone resorption.