Fhl2 deficiency results in osteopenia due to decreased activity of osteoblasts.
Osteoporosis is one of the major health problems today, yet little is known about the loss of bone mass caused by reduced activity of the bone-forming osteoblasts. Here we show that mice deficient for the transcriptional cofactor four and a half LIM domains 2 (Fhl2) exhibit a dramatic decrease of bone mass in both genders. Osteopenia is caused by a reduced bone formation rate that is solely due to the diminished activity of Fhl2-deficient osteoblasts, while their number remains unchanged. The number and activity of the bone-resorbing cells, the osteoclasts, is not altered. Enforced expression of Fhl2 in differentiated osteoblasts boosts mineralization in cell culture and, importantly, enhances bone formation in transgenic animals. Fhl2 increases the transcriptional activity of runt-related transcription factor 2 (Runx2), a key regulator of osteoblast function, and both proteins interact in vitro and in vivo. In summary, we present Fhl2-deficient mice as a unique model for osteopenia due to decreased osteoblast activity. Our data offer a novel concept to fight osteoporosis by modulating the anabolic activity of osteoblasts via Fhl2.
Günther
Thomas
T
Universitäts-Frauenklinik und Zentrum für Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
Poli
Cecilia
C
Müller
Judith M
JM
Catala-Lehnen
Philip
P
Schinke
Thorsten
T
Yin
Na
N
Vomstein
Sandra
S
Amling
Michael
M
Schüle
Roland
R
D000818:Animals; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002113:Calcification, Physiologic; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D010012:Osteogenesis; D011485:Protein Binding; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; C491382:Fhl2 protein, mouse; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors