title: Impaired Fracture Healing Caused by Deficiency of the Immunoreceptor Adaptor Protein DAP12.
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.
authors.affiliation: Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kamimura
authors.affiliation: Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University4-1 Seiryo-machi, Aobaku, Sendai, Miyagi, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Sugahara-Tobinai
authors.affiliation: Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University4-1 Seiryo-machi, Aobaku, Sendai, Miyagi, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
authors.affiliation: Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Itoi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency*; D000818:Animals; D005260:Female; D017102:Fracture Healing; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013977:Tibia / Q000000981:diagnostic imaging / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D013978:Tibial Fractures / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C484963:Tyrobp protein, mouse