Mutations in the insulin-like factor 3 receptor are associated with osteoporosis

Alberto Ferlin; Anastasia Pepe; Lisa Gianesello; Andrea Garolla; Shu Feng; Sandro Giannini; Manuela Zaccolo; Arianna Facciolli; Roy Morello; Alexander I Agoulnik; Carlo Foresta

doi:10.1359/jbmr.080204

Mutations in the insulin-like factor 3 receptor are associated with osteoporosis

Ferlin A, Pepe A, Gianesello L, Garolla A, Feng S, Giannini S, Zaccolo M, Facciolli A, Morello R, Agoulnik AI, Foresta C

Published May 2008 Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

DOI 10.1359/jbmr.080204 PMID 18433302 PMC PMC2674542

RRM Academy Synopsis

INSL3 receptor mutation is linked to low bone density in young men

16 out of 25 young men with an RXFP2 gene mutation had reduced bone density. RXFP2 encodes the receptor for insulin-like factor 3 (INSL3), a hormone made in the testis. The authors compared the 25 men, aged 27–41 years, with two control groups, then tested bone cells and male mice lacking the receptor, which had lower bone mass.

About 6 in 10 young men with the RXFP2 mutation had reduced bone density. Source: Ferlin A et al., 2008, PMID 18433302.

Study at a glance: INSL3 receptor mutation is linked to low bone density in young men. Source: Ferlin A et al., 2008, PMID 18433302.

Key Findings

Among 25 men with the T222P mutation in the RXFP2 gene, 16 (64.0%) had reduced bone mineral density: 10 had osteopenia and 6 had osteoporosis on DXA scanning.
Testosterone, other measured hormones and testicular function were normal in these men, and no other apparent cause of osteoporosis was found.
Bone density was normal in 51 age-matched healthy men and in 20 age-matched men with surgically corrected cryptorchidism and no RXFP2 or INSL3 mutation (p < 0.001 versus the mutation group).
Osteoblasts, the bone-forming cells, expressed RXFP2, and INSL3 stimulation produced dose-dependent increases in cAMP and in osteoblast proliferation.
Male mice lacking Rxfp2 had lower distal femur trabecular bone volume (percent of tissue volume, 15.9 ± 3.0 versus 21.4 ± 3.9 in wildtype, p < 0.01) and lower spinal bone formation.

Interpretation

This study compared 25 men with the RXFP2 T222P gene change to two control groups, then tested bone cells and mice lacking the receptor. The authors did not detect INSL3 in bone tissue, so they think it travels through the blood to act on bone. Only some carriers of the gene change had low bone density. The authors suggest that bone loss builds up over time and depends on other factors too. Larger studies could test this role for INSL3 in men's bone health.

RRM Context

Restorative reproductive medicine examines both partners for causes in the body. This paper gives an example in men. INSL3 is a hormone made in the testis that helps the testes descend before birth. INSL3 also acts on bone, even in men whose testosterone and testicular function are normal.

Our editorial summary of this paper, not the article's abstract.

Abstract

Introduction

Insulin-like factor 3 (INSL3) is produced primarily by testicular Leydig cells. It acts by binding to its specific G protein-coupled receptor RXFP2 (relaxin family peptide 2) and is involved in testicular descent during fetal development. The physiological role of INSL3 in adults is not known, although substantial INSL3 circulating levels are present. The aim of this study was to verify whether reduced INSL3 activity could cause or contribute to some signs of hypogonadism, such as reduced BMD, currently attributed to testosterone deficiency.

Materials and Methods

Extensive clinical, biochemical, and hormonal study, including bone densitometry by DXA, was performed on 25 young men (age, 27-41 yr) with the well-characterized T222P mutation in the RXFP2 gene. Expression analysis of INSL3 and RXFP2 on human bone biopsy and human and mouse osteoblast cell cultures was performed by RT-PCR, quantitative RT-PCR, and immunohistochemistry. Real-time cAMP imaging analysis and proliferation assay under the stimulus of INSL3 was performed on these cells. Lumbar spine and femoral bone of Rxfp2-deficient mice were studied by static and dynamic histomorphometry and muCT, respectively.

Results

Sixteen of 25 (64%) young men with RXFP2 mutations had significantly reduced BMD. No other apparent cause of osteoporosis was evident in these subjects, whose testosterone levels and gonadal function were normal. Expression analyses showed the presence of RXFP2 in human and mouse osteoblasts. Stimulation of these cells with INSL3 produced a dose- and time-dependent increase in cAMP and cell proliferation, confirming the functionality of the RXFP2/INSL3 receptor-ligand complex. Consistent with the human phenotype, bone histomorphometric and muCT analyses of Rxfp2(-/-) mice showed decreased bone mass, mineralizing surface, bone formation, and osteoclast surface compared with wildtype littermates.

Conclusions

This study suggests for the first time a role for INSL3/RXFP2 signaling in bone metabolism and links RXFP2 gene mutations with human osteoporosis.

Topics

Bone Health

Osteoporosis Diagnosis and Treatment

Bone Health › Osteoporosis › Diagnosis and Treatment

Alberto Ferlin, Anastasia Pepe, Lisa Gianesello, Andrea Garolla, Shu Feng, Sandro Giannini, Manuela Zaccolo, Arianna Facciolli, Roy Morello, Alexander I Agoulnik, Carlo Foresta

A Ferlin, A Pepe, L Gianesello, A Garolla, S Feng, S Giannini, M Zaccolo, A Facciolli, R Morello, Alex Agoulnik, A Agoulnik, C Foresta

PMID 18433302 18433302 DOI 10.1359/jbmr.080204 10.1359/jbmr.080204 Ferlin et al. 2008, Ferlin 2008

Mutations in the insulin-like factor 3 receptor are associated with osteoporosis

INSL3 receptor mutation is linked to low bone density in young men

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

Related research