The effects of mechanically loaded osteocytes and inflammation on bone remodeling in a bisphosphonate-induced environment

• Published in: Bone (New York, N.Y.) Vol. 127; pp. 460 - 473
• Main Authors: George, Estee L., Truesdell, Sharon L., Magyar, Alexandria L., Saunders, Marnie M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2019
• Subjects: Bisphosphonate-related osteonecrosis of the jaw; Bone remodeling; Inflammation; Mechanical load; Mechanotransduction; Polydimethylsiloxane; Mechanical load; Bisphosphonate-related osteonecrosis of the jaw; Mechanotransduction; Inflammation; Bone remodeling; Polydimethylsiloxane
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2019.07.008

Bisphosphonate-related osteonecrosis of the jaw is a disease appearing after tooth removal in patients undergoing bisphosphonate treatment for metastasizing cancers and osteoporosis. The complexity of the condition requires a multicellular model to address the net effects of two key risk factors: mechanical trauma (pathologic overload) and inflammation. In this work, a system comprised of a polydimethylsiloxane chip and mechanical loading device is used to expose bisphosphonate-treated osteocytes to mechanical trauma. Specifically, osteocytes are treated with the potent nitrogen-containing bisphosphonate, zoledronic acid, and exposed to short-term pathologic overload via substrate stretch. During bone remodeling, osteocyte apoptosis plays a role in attracting pre-osteoclasts to sites of damage; as such, lactate dehydrogenase activity, cell death and protein expression are evaluated as functions of load. Additionally, the effects of osteocyte soluble factors on osteoclast and osteoblast functional activity are quantified. Osteoclast activity and bone resorption are quantified in the presence and absence of inflammatory components, lipopolysaccharide and interferon gamma. Results suggest that inflammation associated with bacterial infection may hinder bone resorption by osteoclasts. In addition, osteocytes may respond to overload by altering expression of soluble signals that act on osteoblasts to attenuate bone formation. These findings give insight into the multicellular interactions implicated in bisphosphonate-related osteonecrosis of the jaw. •A polymer chip and loading device were developed for exposing osteocytes to overload.•Bisphosphonate-treated loaded osteocytes altered expression of remodeling proteins.•Inflammation, but not osteocyte conditioned medium, altered osteoclast activity.•Osteoblasts exposed to conditioned medium formed less bone than did control cells.•Remodeling attenuated by soluble factors and inflammation may lead to osteonecrosis.