BMP9 stimulates joint regeneration at digit amputation wounds in mice

Yu, Ling; Dawson, Lindsay A.; Yan, Mingquan; Zimmel, Katherine; Lin, Yu-Lieh; Dolan, Connor P.; Han, Manjong; Muneoka, Ken

doi:10.1038/s41467-018-08278-4

Cited by 52 publications

(68 citation statements)

References 54 publications

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“…While there were 20 KEGG pathways significantly enriched in X1, only four pathways were enriched in X2 ( Figure 2F and Supplementary Table S5 ). To confirm the results of the bioinformatics analyses, we quantified the expressions of several genes related to tissue regeneration ( Kroehne et al, 2011 ; Tsujioka et al, 2017 ; Galvao et al, 2018 ; Yu et al, 2019 ). prg4a and klf11 were indeed upregulated only in the lesioned hemisphere ( Figure 2G ), while gfap and il6st were so in both hemispheres ( Figure 2H ).…”

Section: Resultsmentioning

confidence: 99%

Comparative Transcriptome Analysis of the Regenerating Zebrafish Telencephalon Unravels a Resource With Key Pathways During Two Early Stages and Activation of Wnt/β-Catenin Signaling at the Early Wound Healing Stage

Demırcı

Cucun

Poyraz

et al. 2020

Front. Cell Dev. Biol.

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Owing to its pronounced regenerative capacity in many tissues and organs, the zebrafish brain represents an ideal platform to understand the endogenous regeneration mechanisms that restore tissue integrity and function upon injury or disease. Although radial glial and neuronal cell populations have been characterized with respect to specific marker genes, comprehensive transcriptomic profiling of the regenerating telencephalon has not been conducted so far. Here, by processing the lesioned and unlesioned hemispheres of the telencephalon separately, we reveal the differentially expressed genes (DEGs) at the early wound healing and early proliferative stages of regeneration, i.e., 20 h post-lesion (hpl) and 3 days post-lesion (dpl), respectively. At 20 hpl, we detect a far higher number of DEGs in the lesioned hemisphere than in the unlesioned half and only 7% of all DEGs in both halves. However, this difference disappears at 3 dpl, where the lesioned and unlesioned hemispheres share 40% of all DEGs. By performing an extensive comparison of the gene expression profiles in these stages, we unravel that the lesioned hemispheres at 20 hpl and 3 dpl exhibit distinct transcriptional profiles. We further unveil a prominent activation of Wnt/β-catenin signaling at 20 hpl, returning to control level in the lesioned site at 3 dpl. Wnt/β-catenin signaling indeed appears to control a large number of genes associated primarily with the p53, apoptosis, forkhead box O (FoxO), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR) signaling pathways specifically at 20 hpl. Based on these results, we propose that the lesioned and unlesioned hemispheres react to injury dynamically during telencephalon regeneration and that the activation of Wnt/β-catenin signaling at the early wound healing stage plays a key role in the regulation of cellular and molecular events.

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Section: Resultsmentioning

confidence: 99%

Comparative Transcriptome Analysis of the Regenerating Zebrafish Telencephalon Unravels a Resource With Key Pathways During Two Early Stages and Activation of Wnt/β-Catenin Signaling at the Early Wound Healing Stage

Demırcı

Cucun

Poyraz

et al. 2020

Front. Cell Dev. Biol.

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“…Recently, it has been reported that ectopic Fgf signaling can induce intercalary regeneration in chicken limb buds 36 . Likewise, mouse digit tip regeneration can be enhanced by Bmp application 37,38 . These related discoveries imply the existence of a conserved regeneration system across species.…”

Section: Discussionmentioning

confidence: 99%

Neural regulation in tooth regeneration of Ambystoma mexicanum

Makanae

Tajika

Nishimura

et al. 2020

Sci Rep

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the presence of nerves is an important factor in successful organ regeneration in amphibians. the Mexican salamander, Ambystoma mexicanum, is able to regenerate limbs, tail, and gills when nerves are present. However, the nerve-dependency of tooth regeneration has not been evaluated. Here, we reevaluated tooth regeneration processes in axolotls using a three-dimensional reconstitution method called coMBi and found that tooth regeneration is nerve-dependent although the dentary bone is independent of nerve presence. the induction and invagination of the dental lamina were delayed by denervation. Exogenous Fgf2, Fgf8, and Bmp7 expression could induce tooth placodes even in the denervated mandible. our results suggest that the role of nerves is conserved and that fgf+Bmp signals play key roles in axolotl organ-level regeneration. the presence of nerves is an important factor in successful organ regeneration in amphibians. the Mexican salamander, Ambystoma mexicanum, is able to regenerate limbs, tail, and gills when nerves are present. However, the nervedependency of tooth regeneration has not been evaluated. Here, we reevaluated tooth regeneration processes in axolotls using a three-dimensional reconstitution method called coMBi and found that tooth regeneration is nerve-dependent although the dentary bone is independent of nerve presence. the induction and invagination of the dental lamina were delayed by denervation. Exogenous Fgf2, Fgf8, and Bmp7 expression could induce tooth placodes even in the denervated mandible. our results suggest that the role of nerves is conserved and that fgf+Bmp signals play key roles in axolotl organ-level regeneration. The ability to regenerate lost tissues or organs in human patients has long been eagerly desired. Teeth are among the organs for which a novel treatment allowing perfect regeneration would be extremely useful. Due to the unique and multifarious roles of the teeth and associated structures, there has been a sustained effort to find optimal ways to replace missing dentition over many centuries. Amphibian teeth have unique physiological features but maintain some structural and functional similarities to mammalian teeth 1,2. One of the most notable features of amphibian teeth is polyphyodonty. Through polyphyodonty, amphibians replace their teeth continuously during life, whereas each mammalian tooth has either one or two generations (mono-or diphyodonty). Amphibian tooth development has been described in some classic studies 3-10. As far as we know, Hertwig published the first study of amphibian tooth development 5. Recently, the literature on tooth regeneration in amphibians was reviewed 1. The dental lamina is induced from the oral epithelium. The dental lamina, which consists of two layers, invades into the oral mesenchyme. The distal region of the dental lamina interacts with mesenchymal cells and forms a cup that is composed of the outer dental epithelium and the inner dental epithelium. The inner dental epithelium differentiates into enamel organs. The mesenchymal ...

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“…Bone morphogenetic protein 9 (BMP9) (also known as growth differentiation factor 2, or GDF‐2), a member of the transforming growth factor‐β (TGF‐β)/BMP superfamily, is principally produced by the liver and circulates in the bloodstream; its receptors are ALK1 and ALK2 . Recent research has found that BMP9 plays an important role in preventing liver fibrosis, improving heart failure, suppressing tumors, regulating glucose and lipid metabolism, and regenerating joints . More recently, dentinogenetic and tooth‐alveolar bone complex defects in BMP9‐knockout mice were reported, demonstrating the role of BMP9 in the skeletal system.…”

Section: Introductionmentioning

confidence: 99%

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

Zhou

Yang

Jing

et al. 2020

Journal of Bone and Mineral Research

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Bone remodeling is dynamic and is tightly regulated through bone resorption dominated by osteoclasts and bone formation dominated by osteoblasts. Imbalances in this process can cause various pathological conditions, such as osteoporosis. Bone morphogenetic protein 9 (BMP9), a biomolecule produced and secreted by the liver, has many pharmacological effects, including anti-liver fibrosis, antitumor, anti-heart failure, and antidiabetic activities. However, the effects of BMP9 on the regulation of osteoblast and osteoclast functions and the underlying molecular mechanism(s) have not yet been investigated. In this study, BMP9 increased the expression of osteoblastogenic gene markers, such as ALP, Cola1, OCN, RUNX2, and OSX, and ALP activity in MC3T3-E1 cells by upregulating LGR6 and activating the Wnt/β-catenin pathway. BMP9 also suppressed receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation of bone marrow macrophages (BMMs) by inhibiting the Akt-NF-κB-NFATc1 pathway. More importantly, in an ovariectomy (OVX) mouse model, BMP9 attenuated bone loss and improved bone biomechanical properties in vivo by increasing bone-forming activity and suppressing bone resorption activity. Accordingly, our current work highlights the dual regulatory effects that BMP9 exerts on bone remodeling by promoting bone anabolic activity and inhibiting osteoclast differentiation in OVX mice.

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BMP9 stimulates joint regeneration at digit amputation wounds in mice

Cited by 52 publications

References 54 publications

Comparative Transcriptome Analysis of the Regenerating Zebrafish Telencephalon Unravels a Resource With Key Pathways During Two Early Stages and Activation of Wnt/β-Catenin Signaling at the Early Wound Healing Stage

Comparative Transcriptome Analysis of the Regenerating Zebrafish Telencephalon Unravels a Resource With Key Pathways During Two Early Stages and Activation of Wnt/β-Catenin Signaling at the Early Wound Healing Stage

Neural regulation in tooth regeneration of Ambystoma mexicanum

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

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