Toll-like receptor 4 signaling in osteoblasts is required for load-induced bone formation in mice

In mature bone, NGF is produced by osteoblasts following mechanical loading and signals through resident sensory nerves expressing its high affinity recep-tor, neurotrophic tyrosine kinase receptor type 1 (TrkA), to support bone for-mation. Here, we investigated whether osteoblastic expression of Toll-like re-ceptor 4 (TLR4), a key receptor in the NF -KB signaling pathway, is required to initiate NGF-TrkA signaling required for load-induced bone formation. Although Tlr4 conditional knockout mice have normal skeletal mass and strength in adult-hood, the loss of TLR4 signaling significantly reduced lamellar bone formation following loading. Inhibition of TLR4 signaling reduced Ngf expression in pri-mary osteoblasts and RNA sequencing of bones from Tlr4 conditional knockout mice and wild-type littermates revealed dysregulated inflammatory signaling three days after osteogenic mechanical loading. In total, our study reveals an important role for osteoblastic TLR4 in the skeletal adaptation of bone to me-chanical forces.