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This article is the author's final published version in iScience, Volume 26, Issue 4, April 2023, Article number 106304.

The published version is available at Copyright © 2023 The Author(s).


In mature bone, NGF is produced by osteoblasts following mechanical loading and signals through resident sensory nerves expressing its high affinity receptor, neurotrophic tyrosine kinase receptor type 1 (TrkA), to support bone formation. Here, we investigated whether osteoblastic expression of Toll-like receptor 4 (TLR4), a key receptor in the NF-κB 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 adulthood, the loss of TLR4 signaling significantly reduced lamellar bone formation following loading. Inhibition of TLR4 signaling reduced Ngf expression in primary 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 mechanical forces.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Supplemental Information.pdf (943 kB)
Document S1. Figures S1–S8.

1-s2.0-S2589004223003814-mmc2.xlsx (59 kB)
Table S1. Differentially expressed genes, related to Figures 4 and 5.

1-s2.0-S2589004223003814-mmc3.xlsx (23 kB)
Table S2. Gene set enrichment analysis, related to Figure 6.