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IGFBP-4 regulates adult skeletal growth in a sex-specific manner.

ABSTRACT: Insulin-like growth factor-1 (IGF-1) and its binding proteins are critical mediators of skeletal growth. Insulin-like growth factor-binding protein 4 (IGFBP-4) is highly expressed in osteoblasts and inhibits IGF-1 actions in vitro Yet, in vivo studies suggest that it could potentiate IGF-1 and IGF-2 actions. In this study, we hypothesized that IGFBP-4 might potentiate the actions of IGF-1 on the skeleton. To test this, we comprehensively studied 8- and 16-week-old Igfbp4^-/- mice. Both male and female adult Igfbp4^-/- mice had marked growth retardation with reductions in body weight, body and femur lengths, fat proportion and lean mass at 8 and 16 weeks. Marked reductions in aBMD and aBMC were observed in 16-week-old Igfbp4^-/- females, but not in males. Femoral trabecular BV/TV and thickness, cortical fraction and thickness in 16-week-old Igfbp4^-/- females were significantly reduced. However, surprisingly, males had significantly more trabeculae with higher connectivity density than controls. Concordantly, histomorphometry revealed higher bone resorption and lower bone formation in Igfbp4^-/- females. In contrast, Igfbp4^-/- males had lower mineralized surface/bone surface. Femoral expression of Sost and circulating levels of sclerostin were reduced but only in Igfbp4^-/- males. Bone marrow stromal cultures from mutants showed increased osteogenesis, whereas osteoclastogenesis was markedly increased in cells from Igfbp4^-/- females but decreased in males. In sum, our results indicate that loss of Igfbp4 affects mesenchymal stromal cell differentiation, regulates osteoclastogenesis and influences both skeletal development and adult bone maintenance. Thus, IGFBP-4 modulates the skeleton in a gender-specific manner, acting as both a cell autonomous and cell non-autonomous factor.

SUBMITTER: Maridas DE

PROVIDER: S-EPMC5425953 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Accumulating evidence indicates that gut microbiota may regulate sex-hormone levels in the host, with effects on reproductive health. Very little is known about the development of intestinal microbiota during puberty in humans. To assess the connection between pubertal timing and fecal microbiota, and to assess how fecal microbiota develop during puberty in comparison with adult microbiota, we utilized a Finnish allergy-prevention-trial cohort (Flora). Data collected at 13-year follow-up were compared with adult data from a different Finnish cohort. Among the 13-year-old participants we collected questionnaire information, growth data from school-health-system records and fecal samples from 148 participants. Reference adult fecal samples were received from the Health and Early Life Microbiota (HELMi) cohort (n = 840). Fecal microbiota were analyzed using 16S rRNA gene amplicon sequencing; the data were correlated with pubertal timing and compared with data on adult microbiota. Probiotic intervention in the allergy-prevention-trial cohort was considered as a confounding factor only. The main outcome was composition of the microbiota in relation to pubertal timing (time to/from peak growth velocity) in both sexes separately, and similarity to adult microbiota. In girls, fecal microbiota became more adult-like with pubertal progression (p = 0.009). No such development was observed in boys (p = 0.9). Both sexes showed a trend towards increasing relative abundance of estrogen-metabolizing Clostridia and decreasing Bacteroidia with pubertal development, but this was statistically significant in girls only (p = 0.03). In girls, pubertal timing was associated positively with exposure to cephalosporins prior to the age of 10. Our data support the hypothesis that gut microbiota, particularly members of Ruminococcaceae, may affect pubertal timing, possibly via regulating host sex-hormone levels.Trial registration The registration number for the allergy-prevention-trial cohort: ClinicalTrials.gov, NCT00298337, registered 1 March 2006-Retrospectively registered, https://clinicaltrials.gov/show/NCT00298337 . The adult-comparison cohort (HELMi) is NCT03996304.

Project description:BackgroundSexually dimorphic growth has been attributed to the growth hormone (GH)/insulin-like growth factor 1 (IGF1) axis, particularly GH-induced activation of the intracellular signal transducer and activator of transcription 5B (STAT5B), because deletion of STAT5B reduces body mass and the mass of skeletal muscles in male mice to that in female mice. However, it remains unclear why these effects are sex- and species-specific, because the loss of STAT5B retards growth in girls, but not in male mice. Our objectives were to determine whether sexually dimorphic growth of skeletal muscle persisted in STAT5B-/- mice and investigate the mechanisms by which STAT5B regulates sexually dimorphic growth.MethodsBlood and skeletal muscle were harvested from male and female STAT5B-/- mice and their wild-type littermates from the onset of puberty to adulthood.ResultsGrowth of the skeleton and skeletal muscles was retarded in both sexes of STAT5B-/- mice, but more so in males. Although reduced, sexually dimorphic growth of skeletal muscle persisted in STAT5B-/- mice with an oxidative shift in the composition of myofibres in both sexes. Concentrations of IGF1 in blood and skeletal muscle were reduced in male STAT5B-/- mice at all ages, but only in female STAT5B-/- mice at the onset of puberty. Expression of androgen receptor (AR) and oestrogen receptor alpha (ERα) mRNA and protein was reduced in skeletal muscles of male and female STAT5B-/- mice, respectively. Loss of STAT5B abolished the sexually dimorphic expression of myostatin protein and Igf1, Ar, Erα, suppressor of cytokine signalling 2 (Socs2), and cytokine-inducible SH2-containing protein (Cis) mRNA in skeletal muscle.ConclusionsSTAT5B appears to mediate GH signalling in skeletal muscles of male mice at all ages, but only until puberty in female mice. STAT5B also appears to mediate the actions of androgens and oestrogens in both male and female mice, but sexually dimorphic growth persists in STAT5B-/- mice.

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IGFBP-4 regulates adult skeletal growth in a sex-specific manner.

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