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Cilia-related protein SPEF2 regulates osteoblast differentiation.

ABSTRACT: Sperm flagellar protein 2 (SPEF2) is essential for motile cilia, and lack of SPEF2 function causes male infertility and primary ciliary dyskinesia. Cilia are pointing out from the cell surface and are involved in signal transduction from extracellular matrix, fluid flow and motility. It has been shown that cilia and cilia-related genes play essential role in commitment and differentiation of chondrocytes and osteoblasts during bone formation. Here we show that SPEF2 is expressed in bone and cartilage. The analysis of a Spef2 knockout (KO) mouse model revealed hydrocephalus, growth retardation and death prior to five weeks of age. To further elucidate the causes of growth retardation we analyzed the bone structure and possible effects of SPEF2 depletion on bone formation. In Spef2 KO mice, long bones (tibia and femur) were shorter compared to wild type, and X-ray analysis revealed reduced bone mineral content. Furthermore, we showed that the in vitro differentiation of osteoblasts isolated from Spef2 KO animals was compromised. In conclusion, this study reveals a novel function for SPEF2 in bone formation through regulation of osteoblast differentiation and bone growth.

SUBMITTER: Lehti MS

PROVIDER: S-EPMC5770417 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Cilia-related protein SPEF2 regulates osteoblast differentiation.

Lehti Mari S MS Henriksson Henna H Rummukainen Petri P Wang Fan F Uusitalo-Kylmälä Liina L Kiviranta Riku R Heino Terhi J TJ Kotaja Noora N Sironen Anu A

Scientific reports 20180116 1

Sperm flagellar protein 2 (SPEF2) is essential for motile cilia, and lack of SPEF2 function causes male infertility and primary ciliary dyskinesia. Cilia are pointing out from the cell surface and are involved in signal transduction from extracellular matrix, fluid flow and motility. It has been shown that cilia and cilia-related genes play essential role in commitment and differentiation of chondrocytes and osteoblasts during bone formation. Here we show that SPEF2 is expressed in bone and cart ...[more]

PMID: 29339787

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Project description:Developing novel approaches to treat skeletal disorders requires an understanding of how critical molecular factors regulate osteoblast differentiation and bone remodeling. We have reported that (1) retinoic acid receptor-related orphan receptor beta (Ror?) is upregulated in bone samples isolated from aged mice and humans in vivo; (2) Ror? expression is inhibited during osteoblastic differentiation in vitro; and (3) genetic deletion of Ror? in mice results in preservation of bone mass during aging. These data establish that Ror? inhibits osteogenesis and that strict control of Ror? expression is essential for bone homeostasis. Because microRNAs (miRNAs) are known to play important roles in the regulation of gene expression in bone, we explored whether a predicted subset of nine miRNAs regulates Ror? expression during both osteoblast differentiation and aging. Mouse osteoblastic cells were differentiated in vitro and assayed for Ror? and miRNA expression. As Ror? levels declined with differentiation, the expression of many of these miRNAs, including miR-219a-5p, was increased. We further demonstrated that miR-219a-5p was decreased in bone samples from old (24-month) mice, as compared with young (6-month) mice, concomitant with increased Ror? expression. Importantly, we also found that miR-219a-5p expression was decreased in aged human bone biopsies compared with young controls, demonstrating that this phenomenon also occurs in aging bone in humans. Inhibition of miR-219a-5p in mouse calvarial osteoblasts led to increased Ror? expression and decreased alkaline phosphatase expression and activity, whereas a miR-219a-5p mimic decreased Ror? expression and increased osteogenic activity. Finally, we demonstrated that miR-219a-5p physically interacts with Ror? mRNA in osteoblasts, defining Ror? as a true molecular target of miR-219a-5p. Overall, our findings demonstrate that miR-219a-5p is involved in the regulation of Ror? in both mouse and human bone. © 2018 American Society for Bone and Mineral Research.

Dataset Information

Cilia-related protein SPEF2 regulates osteoblast differentiation.

Publications

Cilia-related protein SPEF2 regulates osteoblast differentiation.

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