Fracture healing is accelerated in the absence of the adaptive immune system.

TY - JOUR

T1 - Fracture healing is accelerated in the absence of the adaptive immune system.

AU - Toben, Daniel

AU - Schroeder, Ireen

AU - Thaqif, El Khassawna

AU - Mehta, Manav

AU - Hoffmann, Jan-Erik

AU - Frisch, Jan-Tilmann

AU - Schell, Hanna

AU - Lienau, Jasmin

AU - Serra, Alessandro

AU - Radbruch, Andreas

AU - Duda, Georg N

PY - 2011

Y1 - 2011

N2 - Fracture healing is a unique biologic process starting with an initial inflammatory response. As in other regenerative processes, bone and the immune system interact closely during fracture healing. This project was aimed at further elucidating how the host immune system participates in fracture healing. A standard closed femoral fracture was created in wild-type (WT) and recombination activating gene 1 knockout (RAG1(-/-)) mice lacking the adaptive immune system. Healing was investigated using micro-computed tomography (µCT), biomechanical testing, and histologic and mRNA expression analyses. Biomechanical testing demonstrated a significantly higher torsional moment on days 14 and 21 in the RAG1(-/-) mice compared to the WT group. µCT evaluation of RAG1(-/-) specimens showed earlier mineralization and remodeling. Histologically, endochondral ossification and remodeling were accelerated in the RAG1(-/-) compared with the WT mice. Histomorphometric analysis on day 7 showed a significantly higher fraction of bone and a significantly lower fraction of cartilage in the callus of the RAG1(-/-) mice than in the WT mice. Endochondral ossification was accelerated in the RAG1(-/-) mice. Lymphocytes were present during the physiologic repair process, with high numbers in the hematoma on day 3 and during formation of the hard callus on day 14 in the WT mice. Expression of inflammatory cytokines was reduced in the RAG1(-/-) mice. In contrast, expression of anti-inflammatory interleukin 10 (IL-10) was strongly upregulated in RAG1(-/-) mice, indicating protective effects. This study revealed an unexpected phenotype of enhanced fracture healing in RAG1(-/-) mice, suggesting detrimental functions of lymphocytes on fracture healing. The shift from proinflammatory to anti-inflammatory cytokines suggests that immunomodulatory intervention strategies that maximise the regenerative and minimize the destructive effects of inflammation may lead to enhanced fracture repair.

AB - Fracture healing is a unique biologic process starting with an initial inflammatory response. As in other regenerative processes, bone and the immune system interact closely during fracture healing. This project was aimed at further elucidating how the host immune system participates in fracture healing. A standard closed femoral fracture was created in wild-type (WT) and recombination activating gene 1 knockout (RAG1(-/-)) mice lacking the adaptive immune system. Healing was investigated using micro-computed tomography (µCT), biomechanical testing, and histologic and mRNA expression analyses. Biomechanical testing demonstrated a significantly higher torsional moment on days 14 and 21 in the RAG1(-/-) mice compared to the WT group. µCT evaluation of RAG1(-/-) specimens showed earlier mineralization and remodeling. Histologically, endochondral ossification and remodeling were accelerated in the RAG1(-/-) compared with the WT mice. Histomorphometric analysis on day 7 showed a significantly higher fraction of bone and a significantly lower fraction of cartilage in the callus of the RAG1(-/-) mice than in the WT mice. Endochondral ossification was accelerated in the RAG1(-/-) mice. Lymphocytes were present during the physiologic repair process, with high numbers in the hematoma on day 3 and during formation of the hard callus on day 14 in the WT mice. Expression of inflammatory cytokines was reduced in the RAG1(-/-) mice. In contrast, expression of anti-inflammatory interleukin 10 (IL-10) was strongly upregulated in RAG1(-/-) mice, indicating protective effects. This study revealed an unexpected phenotype of enhanced fracture healing in RAG1(-/-) mice, suggesting detrimental functions of lymphocytes on fracture healing. The shift from proinflammatory to anti-inflammatory cytokines suggests that immunomodulatory intervention strategies that maximise the regenerative and minimize the destructive effects of inflammation may lead to enhanced fracture repair.

KW - Animals

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Cell Differentiation

KW - Biomechanics

KW - X-Ray Microtomography

KW - RNA, Messenger/genetics/metabolism

KW - Cytokines/genetics/metabolism

KW - Osteogenesis/physiology

KW - Adaptive Immunity/immunology

KW - B-Lymphocytes/cytology

KW - Bone Remodeling/physiology

KW - Bony Callus/immunology/radiography

KW - Calcification, Physiologic/physiology

KW - Fracture Healing/immunology

KW - Homeodomain Proteins/metabolism

KW - Immune System/immunology

KW - Inflammation/pathology

KW - Osteoclasts/pathology

KW - T-Lymphocytes/cytology

KW - Animals

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Cell Differentiation

KW - Biomechanics

KW - X-Ray Microtomography

KW - RNA, Messenger/genetics/metabolism

KW - Cytokines/genetics/metabolism

KW - Osteogenesis/physiology

KW - Adaptive Immunity/immunology

KW - B-Lymphocytes/cytology

KW - Bone Remodeling/physiology

KW - Bony Callus/immunology/radiography

KW - Calcification, Physiologic/physiology

KW - Fracture Healing/immunology

KW - Homeodomain Proteins/metabolism

KW - Immune System/immunology

KW - Inflammation/pathology

KW - Osteoclasts/pathology

KW - T-Lymphocytes/cytology

M3 - SCORING: Journal article

VL - 26

SP - 113

EP - 124

JO - J BONE MINER RES

JF - J BONE MINER RES

SN - 0884-0431

IS - 1

M1 - 1

ER -