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.
Highlights
IntroductionOsteoactivin (OA), known as Dchil (dendritic cell-associated, heparin sulfate proteoglycan-dependent integrin ligand), Gpnmb (glycoprotein non-metastatic melanomal protein B), or Hgfin (hematopoietic growth factor-inducible neurokinin 1), is a type 1 transmembrane glycoprotein [1]
Osteoactivin (OA), known as Dchil, Gpnmb, or Hgfin, is a type 1 transmembrane glycoprotein [1]
The transmembrane OAs can be proteolytically cleaved at their juxtamembrane region by extracellular proteases, such as ADAMs [5] and matrix metalloproteinase (MMP) [6], in a process called ectodomain shedding, which results in detachment and release of the extracellular domain to act as cytokines or growth factors [7]
Summary
Osteoactivin (OA), known as Dchil (dendritic cell-associated, heparin sulfate proteoglycan-dependent integrin ligand), Gpnmb (glycoprotein non-metastatic melanomal protein B), or Hgfin (hematopoietic growth factor-inducible neurokinin 1), is a type 1 transmembrane glycoprotein [1]. The OA gene, located on human chromosome 7p15.1 or on mouse chromosome 6 [2], has 11 exons with an open reading frame of 1,716 bp that encodes a protein of 572 amino acid residues It has 13 N-linked glycosylation sites, a heparin binding domain, an integrin-recognition RGD (Arg-GlyAsp) motif in both its extracellular and intracellular domains, and a polycystic kidney disease (PKD) sequence [1,3]. In addition to its diverse roles in normal cells and tissues, aberrant OA expression is linked to various pathological disorders such as glaucoma [17], kidney disease [18], osteoarthritis [19], and several types of cancer, including: uveal melanoma [20], glioma [21], hepatocellular carcinoma [22], and cutaneous melanoma [23]
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