Journal
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 24, Issue 1, Pages 78-86Publisher
WILEY
DOI: 10.1359/JBMR.080902
Keywords
age-related osteoporosis; lamin A/C; osteoblast; osteoclast; RANKL
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Funding
- European Calcified Tissue Society (ECTS)
- ECTS/Amgen fellowship
- Ludwig Boltzmann Institute of Aging Research, Vienna, Austria
- Austrian Science Fund [P20239-B13]
- Deutsche Forschungsgemeinschaft [Ho 1875/5-2]
- DFG Research Center and Cluster of Excellence for Regenerative Therapy Dresden
- Wilhelm Sander-Foundation [2007.005.1]
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Age-related osteoporosis is characterized by low bone mass, poor bone quality, and impaired osteoblastogenesis. Recently, the Hutchinson-Gilford progeria syndrome (HGPS), a disease of accelerated aging and premature osteoporosis, has been linked to mutations in the gene encoding for the nuclear lamina protein lamin A/C. Here, we tested the hypothesis that inhibition of lamin A/C in osteoblastic lineage cells impairs osteoblastogenesis and accelerates osteoclastogenesis. Lamin A/C was knocked-down with small interfering (si)RNA molecules in human bone marrow stromal cells (BMSCs) differentiating toward osteoblasts. Lamin A/C knockdown led to an inhibition of osteoblast proliferation by 26% and impaired osteoblast differentiation by 48%, based on the formation of mineralized matrix. In mature osteoblasts, expression levels of runx2 and osteocalcin mRNA were decreased by lamin A/C knockdown by 44% and 78%, respectively. Furthermore, protein analysis showed that osteoblasts with diminished levels of lamin A/C also secreted less osteocalcin and expressed a lower alkaline phosphatase activity (-50%). Lamin A/C inhibition increased RANKL mRNA and protein levels, whereas osteoprotegerin (OPG) expression was decreased, resulting in an increased RANKL/OPG ratio and an enhanced ability to support osteoclastogenesis, as reflected by a 34% increase of TRACP(+) multinucleated cells. Our data indicate that lamin A/C is essential for proper osteoblastogenesis. Moreover, lack of lamin A/C favors an osteoclastogenic milieu and contributes to enhanced osteoclastogenesis.
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