Skeletal Overexpression of Noggin Results in Osteopenia and Reduced Bone Formation

Abstract

Skeletal cells synthesize bone morphogenetic proteins (BMPs) and BMP antagonists. Noggin is a glycoprotein that binds BMPs selectively and antagonizes BMP actions. Noggin expression in osteoblasts is induced by BMPs and noggin opposes the effects of BMPs on osteoblastic differentiation and function in vitro. However, its effects in vivo are not known. We investigated the direct in vivo effects of noggin on bone remodeling in transgenic mice overexpressing noggin under the control of the osteocalcin promoter. Noggin transgenics suffered long bone fractures in the first month of life. Total, vertebral, and femoral bone mineral densities were reduced by 23-29%. Static and dynamic histomorphometry of the femur revealed that noggin transgenic mice had decreased trabecular bone volume, number of trabeculae, and bone formation rate. Osteoblast surface and number of osteoblasts/trabecular area were not significantly decreased, indicating impaired osteoblastic function. Osteoclast surface and number were normal/decreased, there was no increase in bone resorption, and the tissue had the appearance of woven bone. Vertebral microcomputed tomography scanning confirmed decreased trabecular bone volume and trabecular number. In conclusion, transgenic mice overexpressing noggin in the bone microenvironment have decreased trabecular bone volume and impaired osteoblastic function, leading to osteopenia and fractures.

Noggin Suppression Enhances in Vitro Osteogenesis and Accelerates in Vivo Bone Formation

“…Postnatally, BMP antagonists, have also been found to regulate osteoblast differentiation and adult skeletogenesis. In particular, overexpression or exogenous application of noggin has been shown to severely limit in vitro osteogenesis and in vivo bone formation (23)(24)(25). From a clinical standpoint, however, the utility of osteogenic repression pales in comparison to the overwhelmingly greater need for bone generation.…”

“…In response to BMP-2, -4, or -6, osteoblasts have been shown to dramatically upregulate noggin, suggesting a protective role in negative feedback fashion to limit excessive exposure of cells to BMP signaling (22). In addition, several reports have demonstrated the inhibition of BMP signaling by exogenous application of noggin to significantly impair bone formation both in vitro and in vivo (23)(24)(25). These investigations collectively highlight the capacity of noggin to downregulate BMP activity and inhibit subsequent bone deposition by osteoblasts.…”

The BMP signaling and in vivo bone formation

“…The animals develop osteopenia/ osteoporosis. Significant reductions in bone mineral density, bone volume and bone formation rates are observed in adult transgenic mice (Devlin et al, 2003;Wu et al, 2003).…”

CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia

“…Longitudinal sections, 5 μm thick, were cut on a Microm microtome (Microm, Richards-Allan Scientific, Kalamazoo, MI) and stained with toluidine blue, pH 6.4 or Von Kossa. Static parameters of bone formation and resorption were measured in a defined area between 181 μm and 725 μm from the growth plate, using an OsteoMeasure morphometry system (Osteometrics, Atlanta, GA) [28,29]. For dynamic histomorphometry, mineralizing surface per bone surface and mineral apposition rate were measured in unstained sections under ultraviolet light, using a B-2A set long pass filter consisting of an excitation filter ranging from 450 to 490 nanometers (nm), a barrier filter at 515 nm, and a dichroic mirror at 500 nm.…”