Wnt Proteins Promote Bone Regeneration

Minear, Steven; Leucht, Philipp; Jiang, Jie; Liu, Bo; Zeng, Arial; Fuerer, Christophe; Nusse, Roel; Helms, Jill A.

doi:10.1126/scitranslmed.3000231

Cited by 238 publications

(233 citation statements)

References 64 publications

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“…The administration of Wnt ligand [30] or an antibody which blocks sclerostin leads to an increase in bone mass and strength in rodents [21,[31][32][33] and monkeys [33][34]. Both bone formation in response to trauma and in animals with induced osteoporosis was increased.…”

Section: Discussionmentioning

confidence: 99%

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The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions

Agholme

Isaksson

Kuhstoss

et al. 2011

Bone

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The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unknown if it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, µCT and histology were used for evaluation. The animals were injected with either 10 mg/kg Dkk1-ab or saline every 14 days for 14, 28, or 42 days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28 days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botullinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233 %. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction.

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Section: Discussionmentioning

confidence: 99%

“…of Wnt signaling appears especially beneficial for intramembranous bone formation [30]. If side effects can be avoided -which might be quite possible -Dkk1 antibodies could be used for orthopaedic applications to modulate the healing process.…”

Section: Discussionmentioning

confidence: 99%

The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions

Agholme

Isaksson

Kuhstoss

et al. 2011

Bone

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“…60,61 Endogenous Wnt signaling is also increased in areas of bone healing, and Wnt-filled liposomes can accelerate bone healing. 29 In osteoblast precursor cells, canonical Wnt signaling directly stimulates the Runx2 P1 promoter to drive osteoblast differentiation. 60 Because we showed that NELL-1 significantly increased the nuclear accumulation of bcatenin, it is possible that Runx2 expression may be likewise stimulated to induce osteoblastogenesis.…”

Section: Proposed Molecular Mechanisms Of Nell-1 and Bmp2 Effects On mentioning

confidence: 99%

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Shen

James

Zhang

et al. 2016

The American Journal of Pathology

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The differentiation factor NEL-like molecule-1 (NELL-1) has been reported as osteoinductive in multiple in vivo preclinical models. Bone morphogenetic protein (BMP)-2 is used clinically for skeletal repair, but in vivo administration can induce abnormal, adipose-filled, poorquality bone. We demonstrate that NELL-1 combined with BMP2 significantly optimizes osteogenesis in a rodent femoral segmental defect model by minimizing the formation of BMP2-induced adipose-filled cystlike bone. In vitro studies using the mouse bone marrow stromal cell line M2-10B4 and human primary bone marrow stromal cells have confirmed that NELL-1 enhances BMP2-induced osteogenesis and inhibits BMP2-induced adipogenesis. Importantly, the ability of NELL-1 to direct BMP2-treated cells toward osteogenesis and away from adipogenesis requires intact canonical Wnt signaling. Overall, these studies establish the feasibility of combining NELL-1 with BMP2 to improve clinical bone regeneration and provide mechanistic insight into canonical Wnt pathway activity during NELL-1 and BMP2 osteogenesis. The novel abilities of NELL-1 to stimulate Wnt signaling and to repress adipogenesis may highlight new treatment approaches for bone loss in osteoporosis. NEL-like molecule-1 (NELL-1) is an osteoinductive growth factor first identified through its overexpression in pathologically fusing suture specimens from patients with craniosynostosis. 1,2 Transgenic Nell1-overexpressing mice recapitulate craniosynostosis-like phenotypes, exhibiting gross calvarial bone overgrowth and increased osteoblast differentiation. 3 Conversely, Nell1 deficiency severely disrupts bone growth, as mice with nonsense mutations in Nell1 die perinatally with major skeletal anomalies in the craniofacial complex, spine, and long bones. 4e6 Highlighting the central role of NELL-1 in skeletal development, NELL-1 mediates key downstream effects of the master osteogenic regulator runt-related transcription factor 2 (RUNX2) 7 and can partially rescue RUNX2 loss of function. 8 NELL-1 can also transiently activate mitogen-activated protein kinase signaling to induce RUNX2 phosphorylation and osteogenic differentiation. 9 Recently, we

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“…(42) In vivo, Wnt3a has been shown to accelerate the healing process of bone repair when delivered in liposomes at injury sites. (41) This effect of Wnt3a was mainly the result of enhanced proliferation of skeletal progenitors and acceleration of their differentiation into osteoblasts. Thus, Wntinduced mesenchymal cell proliferation is an important mechanism for enhanced bone formation and fracture repair.…”

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 99%

Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation

Caverzasio

Thouverey

2012

Journal of Bone and Mineral Research

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Previous studies have shown that Wnt3a enhances the proliferation and inhibits the osteogenic differentiation of human mesenchymal stem cells (hMSCs). In this study, we investigated the signaling pathways involved in Wnt3a-induced osteoblastic cell proliferation. Experiments with DKK1, a natural antagonist of Lrp5/6, indicated that Wnt/b-catenin did not play a major role in Wnt3a-induced osteoblastic cell proliferation. The use of selective inhibitors of known mitogenic pathways implicates Src family kinases (SFKs) and a protein kinase C (PKC) in this cellular response. Time-dependent analysis of signaling molecules activated by Wnt3a in MC3T3-E1 cells revealed parallel activation of the canonical pathway and of several tyrosine kinases, including SFKs and PDGF receptors (PDGF-Rs). Functional analysis with specific inhibitors suggested a major role of PDGF-Rs in mediating Wnt3a-induced cell proliferation. Further investigation with an si-RNA approach confirmed a predominant role of this receptor in this cellular response. The use of soluble decoy PDGF-Rs that can sequester extracellular PDGFs excluding that part of the increased PDGF receptor phosphorylation by Wnt3a was the result of autocrine production of PDGFs. A selective SFK inhibitor blunted the enhanced PDGF-R phosphorylation and cell proliferation induced by Wnt3a. Studies of initial events involved in the regulation of this pathway suggest a role of dishevelled. In conclusion, data presented in this study indicate that cell proliferation induced by Wnt3a in osteoblastic cells is mediated by a dishevelleddependent and b-catenin-independent pathway, which involves the transactivation of PDGF receptors. ß

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Wnt Proteins Promote Bone Regeneration

Cited by 238 publications

References 64 publications

The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions

The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation

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