Thrombomodulin functional domains support osteoblast differentiation and bone healing in diabetes in mice

AbstractThrombomodulin (TM) is a transmembrane glycoprotein that contains five functional domains. Soluble TM (sTM), comprising extracellular domains TMD1 (lectin ‐like), TMD2 (EGF‐like repeat containing) and TMD3 (serine‐threonine rich), can be shed from cells by the intramembrane protease rhomboid‐like‐2 (RHBDL2). TM is expressed by osteoblasts, yet its role there has not been determined. Herein we aimed to investigate the properties of TM and its domains in osteoblast function and bone repair following injury in diabetes. In response to a scratch injury of cultured osteoblast‐like MG63 cells, expression of TM and RHBDL2 was enhanced, with increased release of sTM. Conditioned media from the injured cells promoted osteoblast migration, an effect that was lacking with conditioned media from MG63 cells in which TM was silenced by shRNA. Exogenous recombinant TMD1 had no effect on osteoblast activities or on bone repairin vivo. However, TM domains 2 and 3 (TMD2/3), induced MG63 cell migration, proliferation and mineralizationin vitro, and when locally administered in mice, improvedin vivo healing of injured calvarium. This beneficial effect of TMD2/3, mediated via FGFR/ERK signaling pathways, was also observedin vitro under high glucose conditions where endogenous TM expression was reduced, andin vivo in diabetic mice following tibia fracture or calvarium injury, where the osteoblastic response and healing were otherwise dampened. Taken together, osteoblast TM part...
Source: Journal of Bone and Mineral Research - Category: Orthopaedics Authors: Tags: Original Article Source Type: research