Targeted overexpression of osteoactivin in cells of osteoclastic lineage promotes osteoclastic resorption and bone loss in mice.

Abstract

This study sought to test whether targeted overexpression of osteoactivin (OA) in cells of osteoclastic lineage, using the tartrate-resistant acid phosphase (TRAP) exon 1B/C promoter to drive OA expression, would increase bone resorption and bone loss in vivo. OA transgenic osteoclasts showed ∼2-fold increases in OA mRNA and proteins compared wild-type (WT) osteoclasts. However, the OA expression in transgenic osteoblasts was not different. At 4, 8, and 15.3 week-old, transgenic mice showed significant bone loss determined by pQCT and confirmed by μ-CT. In vitro, transgenic osteoclasts were twice as large, had twice as much TRAP activity, resorbed twice as much bone matrix, and expressed twice as much osteoclastic genes (MMP9, calciton receptor, and ADAM12), as WT osteoclasts. The siRNA-mediated suppression of OA expression in RAW264.7-derived osteoclasts reduced cell size and osteoclastic gene expression. Bone histomorphometry revealed that transgenic mice had more osteoclasts and osteoclast surface. Plasma c-telopeptide (a resorption biomarker) measurements confirmed an increase in bone resorption in transgenic mice in vivo. In contrast, histomorphometric bone formation parameters and plasma levels of bone formation biomarkers (osteocalcin and pro-collagen type I N-terminal peptide) were not different between transgenic mice and WT littermates, indicating the lack of bone formation effects. In conclusion, this study provides compelling in vivo evidence that osteoclast-derived OA is a novel stimulator of osteoclast activity and bone resorption.

• Authors: Matilda H-C Sheng, Jon E Wergedal, Subburaman Mohan, Mehran Amoui, David J Baylink, K-H William Lau
• Journal: PloS one (PLoS One) Vol. 7 Issue 4 Pg. e35280 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22536365 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Eye Proteins
• Gpnmb protein, mouse
• Isoenzymes
• Membrane Glycoproteins
• Peptide Fragments
• Procollagen
• procollagen Type I N-terminal peptide
• Osteocalcin
• src-Family Kinases
• Acid Phosphatase
• Acp5 protein, mouse
• Tartrate-Resistant Acid Phosphatase

Topics

• Acid Phosphatase (genetics, metabolism)
• Age Factors
• Animals
• Bone Density
• Bone Resorption (blood, genetics, metabolism)
• Bone and Bones (diagnostic imaging, metabolism, pathology)
• Cell Nucleus Size
• Cell Size
• Eye Proteins (biosynthesis, genetics)
• Female
• Gene Expression
• Isoenzymes (genetics, metabolism)
• Male
• Membrane Glycoproteins (biosynthesis, genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Osteoblasts (metabolism)
• Osteocalcin (blood)
• Osteoclasts (metabolism)
• Peptide Fragments (blood)
• Phenotype
• Procollagen (blood)
• Promoter Regions, Genetic
• Tartrate-Resistant Acid Phosphatase
• X-Ray Microtomography
• src-Family Kinases (metabolism)