Hepatic lipase is expressed by osteoblasts and modulates bone remodeling in obesity.
A number of unexpected molecules were recently identified as products of osteoblasts, linking bone homeostasis to systemic energy metabolism. Here we identify the lipolytic enzyme hepatic lipase (HL, encoded by Lipc) as a novel cell-autonomous regulator of osteoblast function. In an unbiased genome-wide expression analysis, we find Lipc to be highly induced upon osteoblast differentiation, verified by quantitative Taqman analyses of primary osteoblasts in vitro and of bone samples in vivo. Functionally, loss of HL in vitro leads to increased expression and secretion of osteoprotegerin (OPG), while expression of some osteoblast differentiation makers is impaired. When challenging energy metabolism in a diet-induced obesity (DIO) study, lack of HL leads to a significant increase in bone formation markers and a decrease in bone resorption markers. Accordingly, in the DIO setting, we observe in Lipc(-/-) animals but not in wild-type controls a significant increase in lumbar vertebral trabecular bone mass and formation rate as well as in femoral trabecular bone mass and cortical thickness. Taken together, we demonstrate that HL expressed by osteoblasts has an impact on osteoblast OPG expression and that lack of HL leads to increased bone mass in DIO. These data provide a novel and completely unexpected molecular link in the complex interplay of osteoblasts and systemic energy metabolism.
Department of Orthopaedics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Electronic address: abartelt@hsph.harvard.edu.
Alexander
A
Bartelt
Department of Orthopaedics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Electronic address: t.beil@uke.uni-hamburg.de.
F Timo
FT
Beil
Department of Orthopaedics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Electronic address: br.mueller@uke.uni-hamburg.de.
Brigitte
B
Müller
Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Electronic address: t.koehne@uke.uni-hamburg.de.
Till
T
Koehne
Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Electronic address: t.yorgan@uke.de.
Timur A
TA
Yorgan
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Electronic address: ma.heine@uke.uni-hamburg.de.
Markus
M
Heine
Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Electronic address: tayfun.yilmaz@uniklinik-freiburg.de.
Tayfun
T
Yilmaz
Department of Orthopaedics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Electronic address: ruether@uke.uni-hamburg.de.
Wolfgang
W
Rüther
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Electronic address: heeren@uke.uni-hamburg.de.
Joerg
J
Heeren
Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Electronic address: schinke@uke.uni-hamburg.de.
Thorsten
T
Schinke
Department of Orthopaedics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Electronic address: niemeier@uke.uni-hamburg.de.
Andreas
A
Niemeier
D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D016723:Bone Remodeling; D002454:Cell Differentiation; D002478:Cells, Cultured; D059305:Diet, High-Fat; D005247:Feeding Behavior; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology; D008049:Lipase / Q000172:deficiency / Q000378:metabolism*; D008159:Lumbar Vertebrae / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000201:enzymology* / Q000473:pathology*; D009929:Organ Size; D010006:Osteoblasts / Q000201:enzymology* / Q000473:pathology*; D053244:Osteoprotegerin / Q000378:metabolism; D055114:X-Ray Microtomography
D015415:Biomarkers; D053244:Osteoprotegerin; D008049:Lipase; C495700:Lipc protein, mouse
Bone remodeling; Hepatic lipase; Obesity; Osteoblast