Conditional Inactivation of Noggin in the Postnatal Skeleton Causes Osteopenia

Canalis, Ernesto; Brunet, Lisa J.; Parker, Kristen; Zanotti, Stefano

doi:10.1210/en.2011-1604

Cited by 31 publications

(28 citation statements)

References 53 publications

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“…Similarly, overexpression of Noggin, an antagonist of BMP2 and BMP4 in osteoblasts, has been shown to reduce osteoclast number and osteoclastogenesis and increase bone mass (28). This observation is consistent with the recent data of Noggin and Gremlin1 inactivation, which leads to osteopenia (29,30).…”

Section: Blocking Bmp2/4 Signaling Increases Bone Mass As Early Assupporting

confidence: 89%

A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength

Baud’huin

Solban

Cornwall-Brady

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Diseases such as osteoporosis are associated with reduced bone mass. Therapies to prevent bone loss exist, but there are few that stimulate bone formation and restore bone mass. Bone morphogenetic proteins (BMPs) are members of the TGFβ superfamily, which act as pleiotropic regulators of skeletal organogenesis and bone homeostasis. Ablation of the BMPR1A receptor in osteoblasts increases bone mass, suggesting that inhibition of BMPR1A signaling may have therapeutic benefit. The aim of this study was to determine the skeletal effects of systemic administration of a soluble BMPR1A fusion protein (mBMPR1A-mFc) in vivo. mBMPR1A-mFc was shown to bind BMP2/4 specifically and with high affinity and prevent downstream signaling. mBMPR1A-mFc treatment of immature and mature mice increased bone mineral density, cortical thickness, trabecular bone volume, thickness and number, and decreased trabecular separation. The increase in bone mass was due to an early increase in osteoblast number and bone formation rate, mediated by a suppression of Dickkopf-1 expression. This was followed by a decrease in osteoclast number and eroded surface, which was associated with a decrease in receptor activator of NF-κB ligand (RANKL) production, an increase in osteoprotegerin expression, and a decrease in serum tartrate-resistant acid phosphatase (TRAP5b) concentration. mBMPR1A treatment also increased bone mass and strength in mice with bone loss due to estrogen deficiency. In conclusion, mBMPR1A-mFc stimulates osteoblastic bone formation and decreases bone resorption, which leads to an increase in bone mass, and offers a promising unique alternative for the treatment of bone-related disorders.anabolic | therapy B one morphogenetic proteins (BMPs) are members of the TGF-β superfamily that were originally identified by their potent ectopic bone formation activity (1). BMPs regulate cell growth, differentiation, and function (2), and play an important role in regulating normal physiologic functions, although their precise role in bone remodeling remains unclear.BMP signaling is mediated by activation of type I and type II serine-threonine kinase receptors. BMP ligands bind with high affinity to type I receptors followed by heterodimerization with type II receptors, allowing the type II receptor to phosphorylate a short stretch of amino acids in the type I receptor and activate a kinase activity. Activated BMP type I receptor phosphorylates immediate downstream targets, Smad1, Smad5, and Smad8 proteins, which interact with Smad4 and translocate to the nucleus to regulate target gene expression. BMPR1A (or ALK3) is a type I receptor that is known to have high affinity for BMP2 (3) and BMP4 (4), which are expressed in bone; however, the role of BMPR1A in the regulation of BMP2/4 function in the skeleton is unclear.

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Section: Blocking Bmp2/4 Signaling Increases Bone Mass As Early Assupporting

confidence: 89%

A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength

Baud’huin

Solban

Cornwall-Brady

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The sclerostin gene, Sost , is a known target of the BMP signaling pathway, 24 and activation of BMP signaling has been shown to lead to thin bone cortex. 25 Therefore, we sought to determine whether changes in BMP expression, BMP signaling, or both in response to activated noncanonical Wnt signaling might be contributing to the cortical phenotype in Sfrp4 -null mice. Activation of noncanonical signaling by Wnt5a in the osteoblast cell line MC3T3-E1 increased Bmp2 mRNA expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cortical-Bone Fragility — Insights from sFRP4 Deficiency in Pyle’s Disease

et al. 2016

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BACKGROUND Cortical-bone fragility is a common feature in osteoporosis that is linked to nonvertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments. METHODS We evaluated four patients with Pyle’s disease, a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and fractures; two patients were examined by means of exome sequencing, and two were examined by means of Sanger sequencing. After a candidate gene was identified, we generated a knockout mouse model that manifested the phenotype and studied the mechanisms responsible for altered bone architecture. RESULTS In all affected patients, we found biallelic truncating mutations in SFRP4, the gene encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient in Sfrp4, like persons with Pyle’s disease, have increased amounts of trabecular bone and unusually thin cortical bone, as a result of differential regulation of Wnt and bone morphogenetic protein (BMP) signaling in these two bone compartments. Treatment of Sfrp4-deficient mice with a soluble Bmp2 receptor (RAP-661) or with antibodies to sclerostin corrected the cortical-bone defect. CONCLUSIONS Our study showed that Pyle’s disease was caused by a deficiency of sFRP4, that cortical-bone and trabecular-bone homeostasis were governed by different mechanisms, and that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical for achieving proper cortical-bone thickness and stability. (Funded by the Swiss National Foundation and the National Institutes of Health.)

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“…Including the limited half-life of BMP2 and its role in osteoclastogenesis and bone resorption. BMP2 induces osteoclast activity 4 and may cause increased bone turnover in the long term 18 . Here, we studied the effects of a novel mimetic peptide, CK2.3.…”

Section: Discussionmentioning

confidence: 99%

Systemic Injection of CK2.3, a Novel Peptide Acting Downstream of Bone Morphogenetic Protein Receptor BMPRIa, Leads to Increased Trabecular Bone Mass

Akkiraju

Bonor

Olli

et al. 2014

Journal Orthopaedic Research

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Bone Morphogenetic Protein 2 (BMP2) regulates bone integrity by driving both osteogenesis and osteoclastogenesis. However, BMP2 as a therapeutic has significant drawbacks. We have designed a novel peptide CK2.3 that blocks the interaction of Casein Kinase 2 (CK2) with Bone Morphogenetic Protein Receptor type Ia (BMPRIa), thereby activating BMP signaling pathways in the absence of ligand. Here, we show that CK2.3 induced mineralization in primary osteoblast cultures isolated from calvaria and bone marrow stromal cells (BMSCs) of 8 week old mice. Further, systemic tail vein injections of CK2.3 in 8 week old mice resulted in increased bone mineral density (BMD) and mineral apposition rate (MAR). In situ immunohistochemistry of the femur found that CK2.3 injection induced phosphorylation of extracellular signal-related kinase (ERK), but not Smad in osteocytes and osteoblasts, suggesting that CK2.3 signaling occurred through Smad independent pathway. Finally mice injected with CK2.3 exhibited decreased osteoclast differentiation and osteoclast activity. These data indicate that the novel mimetic peptide CK2.3 activated BMPRIa downstream signaling to enhance bone formation without the increase in osteoclast activity that accompanies BMP 2 stimulation.

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Conditional Inactivation of Noggin in the Postnatal Skeleton Causes Osteopenia

Cited by 31 publications

References 53 publications

A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength

A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength

Cortical-Bone Fragility — Insights from sFRP4 Deficiency in Pyle’s Disease

Systemic Injection of CK2.3, a Novel Peptide Acting Downstream of Bone Morphogenetic Protein Receptor BMPRIa, Leads to Increased Trabecular Bone Mass

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