IMPORTANCE:
Pasteurella multocida toxin (PMT) induces degradation of nasal turbinate bones, leading to the syndrome of
atrophic rhinitis. Recently, the molecular mechanism and substrate specificity of PMT were identified. The toxin activates
heterotrimeric G proteins by a covalent modification. However, the mechanism by which PMT induces bone degradation is poorly understood. Our report demonstrates a direct effect of PMT on osteoclast precursor cells, leading to maturation of bone-degrading osteoclasts. Interestingly, PMT stimulates osteoclastogenesis independently of the
cytokine RANKL, which is a key factor in induction of osteoclast differentiation. This implicates a noncanonical osteoclastogenic signaling pathway induced by PMT. The elucidated Gαq/11-dependent osteoclastogenic signal transduction pathway ends in osteoclastogenic NFAT signaling. The noncanonical,
heterotrimeric G protein-dependent osteoclast differentiation process may be of pharmacological relevance, as members of this pathway are highly druggable. In particular, modulation of
G protein-coupled receptor activity in osteoclast progenitors by small molecules might be of specific interest.