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Abstract
Recent studies suggest that the commensal microbiota affects not only host energy metabolism and development of immunity but also bone remodeling by positive regulation of osteoclast activity. However, the mechanism of regulation of bone cells by the commensal microbiota has not been elucidated. In this study, 8-week-old specific pathogen-free (SPF) and germ-free (GF) mice were compared in terms of alveolar bones and primary osteoblasts isolated from calvarias. Micro-CT analysis showed that SPF mice had larger body size associated with lower bone mineral density and bone volume fraction in alveolar bones compared with GF mice. Greater numbers of osteoclasts in alveolar bone and higher serum levels of tartrate-resistant acid phosphatase 5b were observed in SPF mice. Tissue extracts from SPF alveolar bone showed higher levels of cathepsin K, indicating higher osteoclast activity. SPF alveolar extracts also showed elevated levels of γ-carboxylated glutamic acid–osteocalcin as a marker of mature osteoblasts compared with GF mice. Polymerase chain reaction (PCR) array analysis of RNA directly isolated from alveolar bone showed that in SPF mice, expression of mRNA of osteocalcin, which also acts as an inhibitor of bone mineralization, was strongly enhanced compared with GF mice. Cultured calvarial osteoblasts from SPF mice showed reduced mineralization but significantly enhanced expression of mRNAs of osteocalcin, alkaline phosphatase, insulin-like growth factor-I/II, and decreased ratio of osteoprotegerin/receptor activator of nuclear factor-kappa B ligand compared with GF mice. Furthermore, PCR array analyses of transcription factors in cultured calvarial osteoblasts showed strongly upregulated expression of Forkhead box g1. In contrast, Gata-binding protein 3 was strongly downregulated in SPF osteoblasts. These results suggest that the commensal microbiota prevents excessive mineralization possibly by stimulating osteocalcin expression in osteoblasts, and enhances both osteoblast and osteoclast activity by regulating specific transcription factors.
Highlights
All mammals are exposed to environmental microorganisms, known as the commensal microbiota, after birth, and these organisms play important roles in maintaining homeostasis, such as in energy homeostasis [1] and innate immunity [2]
We demonstrated that cultured specific pathogen-free (SPF) osteoblasts exhibit a lower Opg/Rankl ratio and enhanced expression of alkaline phosphatase (Alp) related to differentiation of osteoblasts [22]
Our results suggest that the microbiota directly induces insulin-like growth factor (IGF)-1 and -2 expression in osteoblasts, which supports postnatal growth
Summary
All mammals are exposed to environmental microorganisms, known as the commensal microbiota, after birth, and these organisms play important roles in maintaining homeostasis, such as in energy homeostasis [1] and innate immunity [2]. Recent studies suggest that the commensal microbiota can influence bone remodeling [3,4,5,6]. Germ-free (GF) animals provide an invaluable experimental tool for examining interactions between a host and its microbiota. GF mice have hypoplastic Peyer’s patches, with reduced numbers of IgA-producing plasma cells and lamina propria CD4+ T cells [7]. GF mice have reduced adiposity and improved tolerance to glucose and insulin when compared to conventional specific pathogen-free (SPF) mice [8]. The term “osteomicrobiology” has recently been proposed by Ohlsson et al [9] and Jones et al [10]
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