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J Biol Regul Homeost Agents. 2019 Jul-Aug;33(4):1105-1111.

Abnormal bone architecture in mice expressing MyD88 in cells of the osteoclast lineage.

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Department of Orthopedics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
Hospital for Special Surgery, New York, NY, USA.
present address: School of Dental Medicine, University of Pittsburg, Pittsburg, PA, USA.
Julius Wolff Institute and Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Research Division, Department of Trauma Surgery, University Hospital Jena, Jena, Germany.
Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
present address: Institute of Experimental Genetics, Helmholtz Center Munich, Neuherberg, Germany.


The adapter protein myeloid differentiation primary response gene 88 (MyD88) links the intracellular domains of interleukin receptors 1 and 18, and most Toll-like receptors (TLRs) to interleukin 1 receptor associated kinase (IRAK) signaling and subsequent NF-κB-mediated transcription. Previous work showed that mice with global deficiency of MyD88 (MyD88-/-) have osteopenic cancellous bone along with a reduction in osteoblastic but also osteoclastic surfaces. To further elucidate the role of MyD88 in bone, we utilized mice with osteoclast-restricted MyD88 expression in bone (MyD88OC). Bones of MyD88OC and wild type (wt) mice were examined by microCT analysis. Mechanical properties of bones were tested by three-point bending, and gene expression measured using quantitative real-time polymerase chain reaction. In MyD88OC mice, no osteopenic traits were observed, however, a drastic reduction in geometric parameters was detected. In trabecular bone a loss of connectivity density (-44%, p less than 0.0001) was measured and in cortical bone Imax (-31%, p less than 0.0001), Imin (-20%, p less than 0.001), J (-26%, p less than 0.0001) were reduced. Mechanical testing showed increased load to failure (77%, p less than 0.01) and decreased deflection at failure (-68%, p less than 0.01) of the femur. On the molecular level, relative gene expression analysis showed a (-29%, p less than 0.01) reduction in receptor activator of nuclear factor κ B ligand (RANKL) and no difference in osteoprotegerin (OPG) or RANK. Further, the bone resorption markers cathepsin K (CTSK) and tartrate-resistant acid phosphatase 5 (TRAP) were unchanged. In contrast, the bone formation markers collagen type 1 (COL1A1) and osteocalcin (OC) were decreased by -72% (p less than 0.0001) and -82% (p less than 0.0001), respectively. Together, our data suggests that the function of MyD88 in osteoclasts is sufficient to maintain bone mass, while it fails to preserve bone geometry, likely through dysfunctions in osteoblasts.


MyD88 (myeloid differentiation primary response 88); TLR (toll-like receptor) signaling; bone; bone architecture; osteoblast; osteoclast

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