Bone Abstracts

Infections within or in the vicinity of the skeleton induce osteolytic diseases such as periodontitis, septic arthritis, osteomyelitis. Although host production of osteotropic cytokines is crucial, the precise mechanism by which pathogen associated molecular patterns induce osteoclastogenesis and bone loss is not fully understood. Recognition of these molecules by pattern recognition receptors is highly preserved through evolution with trans-membrane Toll-like receptor (TLR) family as the key component. Many infectious bacteria express flagella for motility and sensing with flagellin as the principal substituent recognized by TLR5. We have studied how activation of TLR 5 affects bone resorption, osteoblasts and osteoclast progenitors.

TLR5 activation by flagellin from S. Typhimurim and B. Subtilis increased ⁴⁵Ca-release from mouse calvarial bones. This was associated with increased expression of the osteoclastic genes Acp5, Ctsk, Oscar, and C-Fos and enhanced bone matrix degradation, as assessed by release of the collagen fragment CTX. The TLR5 agonists increased the mRNA and protein expression of RANKL and reduced OPG mRNA and protein. Recombinant OPG inhibited ⁴⁵Ca-release triggered by TLR5 activation. TLR5 activation also increased mRNA expression of Cox2, but flagellin induced bone resorption was independent of prostaglandins. Osteoblasts isolated from the periosteum of calvarial bones expressed Tlr5 mRNA and stimulation of these cells with flagellin induced Rankl mRNA and suppressed Opg mRNA.

In contrast to activation of TLR4, which results in robust inhibition of RANKL stimulated osteoclast formation in mouse bone marrow macrophage cultures (BMM), TLR5 stimulation did not inhibit RANKL signaling in early osteoclast progenitors. Similar to activation of TLR4, TLR5 agonists stimulated osteoclast formation in RANKL-primed BMM.

These data show that TLR5-signaling stimulates periosteal osteoclast formation and bone resorption by enhancing RANKL/OPG ratio in osteoblasts and enhances osteoclastogenesis in RANKL-primed BMM.