Abstract
Osteoclasts play an important role in bone metabolism, but their exact role in fracture healing remains unclear. DAP12 is an immunoadaptor protein with associated immunoreceptors on myeloid lineage cells, including osteoclasts. Its deficiency causes osteopetrosis due to suppression of osteoclast development and activation. In this report, we assessed the impact of DAP12 on the fracture healing process using C57BL/6 (B6) and DAP12–/– mice. Healing was evaluated using radiography, micro-CT, histology, immunohistochemistry and real-time RT-PCR. Radiography showed lower callus volume and lower callus radiolucency in DAP12–/– mice during later stages. Micro-CT images and quantitative structural analysis indicated that DAP12–/– mice developed calluses of dense trabecular structures and experienced deteriorated cortical shell formation on the surface. Histologically, DAP12–/– mice showed less cartilaginous resorption and woven bone formation. In addition, prominent cortical shell formation was much less in DAP12–/– mice. Immunohistochemistry revealed lower invasion of F4/80 positive monocytes and macrophages into the fracture hematoma in DAP12–/– mice. The expression levels of Col1a1, Col2a1 and Col10a1 in DAP12–/– mice increased and subsequently became higher than those in B6 mice. There was a decrease in the gene expression of Tnf during the early stages in DAP12–/– mice. Our results indicate that DAP12 deficiency impairs fracture healing, suggesting a significant role of DAP12 in the initial inflammatory response, bone remodeling and regeneration.
Highlights
Post-menopausal osteoporosis is a pathological condition that is caused by a deficiency in estrogen and that induces rapid bone resorption; the subsequent osteoporosis increases fracture risk
Compared with between C57BL/6 (B6) mice, DNAX-activation protein 12 (DAP12)–/– mice showed lower callus volume and radiolucency at days 21 and 28. These findings suggested that Original cortical bone resorption was delayed in DAP12–/– mice at day 28
The present study explored the effect of the defect in DAP12 on fracture healing in mice
Summary
Post-menopausal osteoporosis is a pathological condition that is caused by a deficiency in estrogen and that induces rapid bone resorption; the subsequent osteoporosis increases fracture risk. We hypothesized that DAP12 impairment affects both soft callus formation and hard callus remodeling, and that different radiological, histological and molecular biological patterns would be observed between C57BL/6 (B6) mice and DAP12-deficient (DAP12–/–) mice during the healing process. To test this hypothesis, we assessed bone healing in murine tibia fractures in B6 and DAP12–/– mice using radiological, histological and gene expression analyses
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