Figure 1. Osteoclast formation in the context of rheumatoid arthritis.

Monocytes are a type of immune cell (light purple shape) that can develop into osteoclasts (dark purple shape), cells that can degrade healthy bone to initiate remodeling. In certain conditions, such as rheumatoid arthritis, the activity of osteoclasts is increased, which leads to progressive bone loss. Zhang et al. identified two subsets of monocytes. One subset (RANK⁺TLR2⁺) overexpressed two relevant signaling molecules, RANK and TLR2, and is involved in bone resorption. When RANK is activated by RANKL in this subset, the enzyme responsible for TLR2 sialylation (ST3GAL4) becomes upregulated through a molecule called c-Fos (a transcription factor critical for the regulation of osteoclast differentiation). Consequently, TLR2 undergoes sialylation, a process that adds sialic acids that enable TLR2 to bind with different molecules in order to allow fusion of cells. Blocking sialyation or TLR2 with specific molecules (C29 and soyasaponin Bb, respectively) prevents mature osteoclasts from forming and the bone remains intact. The other monocyte subset (RANK⁺TLR2^-) exhibited high levels of RANK but low levels of TLR2. In this subset, RANKL prompts the monocytes to differentiate into pre-osteoclasts that express a molecule called TRAP+, but they fail to mature into fully-functional osteoclasts. Instead, these cells have anabolic properties and promote the production of new bone and blood vessels. This figure was generated using BioRender.com.