Luteinizing Hormone Receptor Knockout (LuRKO) Mice and Transgenic Human Chorionic Gonadotropin (hCG)-Overexpressing Mice (hCG αβ+) Have Bone Phenotypes

• Published in: Endocrinology (Philadelphia) Vol. 144; no. 8; pp. 3555 - 3564
• Main Authors: Yarram, S. J, Perry, M. J, Christopher, T. J, Westby, K, Brown, N. L, Lamminen, T, Rulli, S. B, Zhang, F.-P, Huhtaniemi, I, Sandy, J. R, Mansell, J. P
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-08-2003; Oxford University Press
• Subjects: Adult; Animals; Biological and medical sciences; Bone and Bones - physiology; Bone Density - physiology; Bone growth; Bone histomorphometry; Bone mineral density; Bone resorption; Bone turnover; Cell Line; Cells, Cultured; Chorionic gonadotropin; Chorionic Gonadotropin - genetics; Chorionic Gonadotropin - pharmacology; Chorionic Gonadotropin - physiology; Chronic exposure; Cyclic AMP - biosynthesis; Female; Females; Follicle-stimulating hormone; Fundamental and applied biological sciences. Psychology; Gonadotropins; Hormones; Humans; Leydig Cell Tumor; Luteinizing hormone; Luteinizing Hormone - metabolism; Male; Males; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Osteoblasts; Osteoblasts - chemistry; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteogenesis; Ovariectomy; Ovary - chemistry; Phenotype; Phenotypes; Phosphorylation; Pituitary (anterior); Rats; Receptors; Receptors, LH - analysis; Receptors, LH - deficiency; Receptors, LH - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Sex; Sex hormones; Skeleton; Steroids; Transgenic mice; Tumor Cells, Cultured; Western blotting
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2003-0036

Considerable attention has been paid to the role of sex steroids during periods of major skeletal turnover, but the interaction of the gonadotropic hormones, which include LH, FSH, and human chorionic gonadotropin (hCG), within bone tissue have been overlooked. The question is pertinent due to the recent detection of extragonadal expression of gonadotropin receptors. Western blotting, immunolocalization, and RT-PCR supported the presence of osteoblast LH receptors. However, osteoblast cells failed to bind [125I]hCG and treatment with hCG failed to generate either cAMP or phosphorylated ERK 1/2. Bone mineral density (BMD) and bone histomorphometry were examined in the following models: 1) LH receptor null mutant (LuRKO) mice; 2) transgenic mice overexpressing hCG (hCG αβ+); and 3) ovariectomized (OVX) hCG αβ+ model. Male LuRKO mice showed a decrease in BMD after 5 months, apparently secondary to suppressed gonadal steroid production. Similarly, 9- to 10-wk-old female LuRKO mice exhibited decreases in histomorphometric parameters tested. The data indicate that loss of LH signaling results in a reduction in bone formation or an increase in bone resorption. By contrast, there were significant increases in BMD and histomorphometric indices for female, but not male, hCG αβ+ mice, indicating that chronic exposure to hCG results in bone formation or a decrease in bone resorption. However, OVX of the hCG αβ+ mice resulted in a significant reduction in BMD comparable to OVX WT controls. Although gonadotropin levels are tightly linked to sex steroid titers, it appears that their effects on the skeleton are indirect.