Exendin-4 increases bone mineral density in type 2 diabetic OLETF rats potentially through the down-regulation of SOST/sclerostin in osteocytes.
OBJECTIVE
Glucagon-like peptide-1 (GLP-1) receptor participates in the control of bone resorption in GLP-1 knockout mice. Also, GLP-1 induces an insulin- and parathyroid hormone-independent osteogenic action through osteoclasts and osteoblasts in insulin-resistant and type 2 diabetic rats. Osteocytes are now considered central to bone homeostasis. A secreted product of osteocytes, sclerostin, inhibits bone formation. However, the effect of GLP-1 on osteocytes remains unclear. Therefore, we investigated the effect of GLP-1 on bone mineral density (BMD), and the cellular and molecular mechanisms associated with osteocytes.


METHODS
We investigated the presence of GLP-1 receptors in osteocyte-like MLO-Y4 cells and osteocytes of rat femurs through RT-PCR, Western blot and confocal microscopy, and investigated the effect of exendin-4 on the expression of mRNA (by quantitative real-time RT-PCR) and protein (by Western blot) of SOST/sclerostin in osteocyte-like MLO-Y4 cells during culture under normal or high-glucose (30 mM) conditions, and measured circulating levels of sclerostin, osteocalcin, and tartrate-resistant alkaline phosphatase (TRAP) 5b and femoral BMD in type 2 diabetic OLETF rats treated with exendin-4.


RESULTS
GLP-1 receptor was present on MLO-Y4 cells and osteocytes of rat femurs. Exendin-4 reduced the mRNA expression and protein production of SOST/sclerostin under normal or high-glucose conditions in MLO-Y4 cells. Exendin-4 reduced serum levels of sclerostin, increased serum levels of osteocalcin, and increased femoral BMD in type 2 diabetic OLETF rats.


CONCLUSIONS
These findings suggest that exendin-4 might increase BMD by decreasing the expression of SOST/sclerostin in osteocytes in type 2 diabetes.
Imaging Science based Lung and Bone Disease Research Center, Wonkwang University, Iksan, Jeonbuk, Republic of Korea.
Ju-Young
JY
Kim
Seong-Kyu
SK
Lee
Kyung-Jin
KJ
Jo
Dae-Yong
DY
Song
Dong-Mee
DM
Lim
Keun-Young
KY
Park
Lynda F
LF
Bonewald
Byung-Joon
BJ
Kim
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D015519:Bone Density / Q000187:drug effects*; D019485:Bone Morphogenetic Proteins / Q000097:blood / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D000077270:Exenatide; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects*; D005819:Genetic Markers; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D015675:Osteocalcin / Q000097:blood; D010011:Osteocytes / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D020334:Rats, Inbred OLETF; D060888:Real-Time Polymerase Chain Reaction; D018027:Receptors, Glucagon / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014688:Venoms / Q000494:pharmacology*
D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; C486031:Sost protein, rat; D014688:Venoms; D015675:Osteocalcin; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide