Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice

Xue-bin, WU; Li, Yanan; Schneider, Adina E.; Yu, Wanqin; Rajendren, Gopalan; Iqbal, Jameel; Yamamoto, Masahide; Alam, M. Masihul; Brunet, Lisa J.; Blair, Harry C.; Zaidi, Mone; Abe, Etsuko

doi:10.1172/jci15543

Cited by 197 publications

(87 citation statements)

References 43 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…From a clinical perspective, translation of these findings may ultimately depend on the definition of a means by which this strategy can be delivered to sites of need. And beyond the repair bone defects, a multitude of pathologic states, such as osteoporosis and associated osteopenia, in which a chronic imbalance between the expression of BMP agonists and antagonists potentially exists, similar benefit may be derived through the suppression of noggin (25).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Wan

Pomerantz

Brunet

et al. 2007

Journal of Biological Chemistry

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142

113

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Several investigations have demonstrated a precise balance to exist between bone morphogenetic protein (BMP) agonists and antagonists, dictating BMP signaling and osteogenesis. We report a novel approach to manipulate BMP activity through a down-regulation of the potent BMP antagonist Noggin, and examined the effects on the bone forming capacity of osteoblasts. Reduction of noggin enhanced BMP signaling and in vitro osteoblast bone formation, as demonstrated by both gene expression profiles and histological staining. The effects of noggin suppression on in vivo bone formation were also investigated using critical-sized calvarial defects in mice repaired with noggin-suppressed osteoblasts. Radiographic and histological analyses revealed significantly more bone regeneration at 2 and 4 weeks post-injury. These findings strongly support the concept of enhanced osteogenesis through a down-regulation in Noggin and suggest a novel approach to clinically accelerate bone formation, potentially allowing for earlier mobilization of patients following skeletal injury or surgical resection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Wan

Pomerantz

Brunet

et al. 2007

Journal of Biological Chemistry

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142

113

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“…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).…”

Section: Negative Regulation Of Bmp Signalingmentioning

confidence: 99%

The BMP signaling and in vivo bone formation

Cao

Chen

2005

Gene

273

197

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Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor β(TGFβ) superfamily. The roles of BMPs in embryonic development and cellular functions in postnatal and adult animals have been extensively studied in recent years. Signal transduction studies have revealed that Smads 1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction. Studies from transgenic and knockout mice and from animals and humans with naturally occurring mutations in BMPs and their signaling molecules have shown that BMP signaling plays critical roles in bone and cartilage development and postnatal bone formation. BMP activities are regulated at different molecular levels. Tissue-specific knockout of a specific BMP ligand, a subtype of BMP receptors or a specific signaling molecule is required to further determine the specific role of a BMP ligand, receptor or signaling molecule in a particular tissue.

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“…Noggin has been shown to be expressed in mineralizing tissue, and in in vivo experiments an essential role in joint formation was established (4 -9). The overexpression of either sclerostin or noggin in bone cells leads to osteopenia in rodents, demonstrating the importance of BMP proteins in bone homeostasis and suggesting that sclerostin and noggin function as negative regulators of bone density (3,4,9).BMPs have been shown to induce the expression of BMP antagonists in mesenchymal (preosteoblastic) and osteoblastic cell lines (10,11). In vivo, the highest expression of sclerostin in adult human bone was seen in hypertrophic chondrocytes and osteocytes throughout the skeleton (3).…”

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confidence: 99%

Noggin and Sclerostin Bone Morphogenetic Protein Antagonists Form a Mutually Inhibitory Complex

Winkler

Geoghegan

et al. 2004

Journal of Biological Chemistry

105

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Noggin and sclerostin are bone morphogenetic protein (BMP) antagonists that modulate mitogenic activity through sequestering BMPs. Little is known of the interactions among this class of proteins. We show that recombinant sclerostin and noggin bound to each other with high affinity (K D ‫؍‬ 2.92 nM). This observation has been extended to naturally expressed noggin and sclerostin from the rat osteosarcoma cell line, ROS 17/ 2.8, supporting a role for the complex in natural systems. The noggin-sclerostin complex was competitive with BMP binding and mutually attenuated the activity of each BMP antagonist. Collectively, the data demonstrate a novel and exquisite paradigm for the regulation of BMP activity through direct neutralization of the BMP and activation by co-localized BMP antagonist expression. The pleiotrophic nature of noggin and sclerostin represents a novel mechanism for the fine-tuning of BMP activity in bone homeostasis.Sclerostin, the protein product of the SOST gene, is absent in sclerosteosis, a skeletal disease characterized by bone overgrowth and strong dense bones (1, 2). We have demonstrated that sclerostin, a bone morphogenetic protein (BMP) 1 antagonist highly expressed by osteocytes, is a key regulator of bone formation in vivo and in vitro (3). A number of BMP antagonists have been described that historically were associated with important regulatory activity in developmental systems. Recent studies have expanded the roles of these proteins beyond the described embryonic roles. Noggin has been shown to be expressed in mineralizing tissue, and in in vivo experiments an essential role in joint formation was established (4 -9). The overexpression of either sclerostin or noggin in bone cells leads to osteopenia in rodents, demonstrating the importance of BMP proteins in bone homeostasis and suggesting that sclerostin and noggin function as negative regulators of bone density (3,4,9).BMPs have been shown to induce the expression of BMP antagonists in mesenchymal (preosteoblastic) and osteoblastic cell lines (10,11). In vivo, the highest expression of sclerostin in adult human bone was seen in hypertrophic chondrocytes and osteocytes throughout the skeleton (3). In comparison, in vivo, noggin expression was reported to be associated with chondrocytes (12) and osteoblasts of cranial sutures (7). Given the close localization of these two BMP antagonist proteins and the similarity of their activities in vitro, we asked how these proteins might interact in regulating bone formation via limiting BMP activity. We report that these proteins coordinate their activity but do so through an unexpected pathway. Sclerostin and noggin bind to each other with high affinity and attenuate the BMP antagonist activity of each other. We propose that these BMP antagonists are pleiotrophic. EXPERIMENTAL PROCEDURESThe Binding of Noggin and Sclerostin-Anti-FLAG M2-agarose beads (Sigma) were washed with IP buffer (20 mM Tris, pH 7.6, 150 mM NaCl, 1 mM EDTA, 1% Triton X-100, 1.4 mM ␤ME, 10% glycerol) before incubation in t...

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Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice

Cited by 197 publications

References 43 publications

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

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

The BMP signaling and in vivo bone formation

Noggin and Sclerostin Bone Morphogenetic Protein Antagonists Form a Mutually Inhibitory Complex

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