Lipoprotein components of probiotics act as negative regulators of bone metabolism via the dual modulation of osteoclast and osteoblast differentiation.

Bacterial lipoproteins are recognized as key virulence factors that contribute to bone destruction during bacterial infection. Probiotics are widely known for their beneficial effects on bone health; however, the role of their lipoproteins remains poorly understood. In the current study, we investigated the role of lipoproteins derived from the representative probiotic Lactiplantibacillus plantarum (Lp.lpp) in the regulation of bone metabolism. A lipoprotein-enriched fraction was prepared from L. plantarum by sonication followed by Triton X-114 phase separation. Intraperitoneal administration of Lp.lpp led to substantial trabecular bone loss, accompanied by increased tartrate-resistant acid phosphatase-positive areas and reduced Runx2 expression. Lp.lpp also promoted bone resorption in a mouse calvarial implantation model. Lp.lpp increased osteoclast differentiation and suppressed osteoblast differentiation, as evidenced by reduced Runx2 expression and impaired osteoblast maturation. Moreover, Lp.lpp elevated osteoclast differentiation and the receptor activator of nuclear factor κB ligand/osteoprotegerin ratio in an osteoclast/osteoblast co-culture system, favoring osteoclastogenesis. Lipoproteins derived from other probiotic strains, including Limosilactobacillus reuteri, Lacticaseibacillus rhamnosus GG, and Lacticaseibacillus casei, also induced osteoclast differentiation, indicating a generalized enhancement of osteoclast differentiation across probiotic-derived lipoproteins. Collectively, although beneficial probiotics have been reported to support bone health by suppressing bone resorption and promoting bone formation, their lipoprotein components may act as potential risk factors compromising bone integrity, particularly under inflammatory or dysbiotic conditions, where bacterial lipoproteins are extensively recognized by bone and immune cells.