Mesenchymal Cell-Derived Juxtacrine Wnt1 Signaling Regulates Osteoblast Activity and Osteoclast Differentiation

Wang, Fan; Tarkkonen, Kati; Nieminen-Pihala, Vappu; Nagano, Kenichi; Majidi, Rana Al; Puolakkainen, Tero; Rummukainen, Petri; Lehto, Jemina; Roivainen, Anne; Zhang, Fuping; Mäkitie, Outi; Baron, Roland; Kiviranta, Riku

doi:10.1002/jbmr.3680

Cited by 37 publications

(30 citation statements)

References 47 publications

(72 reference statements)

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“…Notum acts as a negative regulator of Wnt signaling pathway by specifically mediating depalmitoleoylation of Wnts (2). Wnt1 activates canonical Wnt/β-catenin signaling via LRP5/6 receptors by cell-cell physical contact and regulates osteoclastogenesis with OPG in a juxtacrine manner (11). By binding to cell surface receptors, Wnt1 activates a canonical signaling pathway that increases cellular β-catenin activity.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive bioinformatic analysis of Wnt1 and Wnt1-associated diseases

Peng

Ren

et al. 2020

IRDR

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Wnt1 is the first member of the Wnt family that was identified. It is phylogenetically conserved and essential for oncogenesis and multiple developmental processes. This study has summarized diseases and mutations related to Wnt1. Wnt1 is involved in various cancers, genetic type XV osteogenesis imperfecta, osteoporosis, and neurological diseases. The expression of Wnt1 in normal tissues and different types of cancers and the potential survival of cancer were analyzed using experiment-based bioinformatic analysis. Systematic analysis indicated that abnormal expression of Wnt1 is significantly associated with cancers, such as kidney renal carcinoma, hepatocellular carcinoma, thyroid carcinoma, head and neck squamous cell carcinoma, and uterine corpus endometrial carcinoma. GeneMANIA and STRING predicted that 32 proteins were involved with Wnt1 in Wnt signaling pathways and sorting and secretion of Wnts. These interacting molecules significantly co-occurred according to cBioPortal analysis. Thirty-three genes with an alteration frequency of more than 50% were observed in several cancers like esophageal squamous cell carcinoma, melanoma, and non-small cell lung cancer. Functional and experiment-based bioinformatics indicated that Wnt1 may act as a target of a potential biomarker for various types of human cancers. Wnt1 and other Wnt1-related proteins and signaling pathways may be ways to treat osteoporosis.

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Section: Discussionmentioning

confidence: 99%

“…Knockout mice of the homozygous Int-1 displayed a severe phenotype, ranging from death to ataxia (10). Conditional knockout of Wnt1 in mesenchymal progenitors led to severe fractures in mice resembling severe osteogenesis imperfecta (OI) (11). Overexpression of Wnt1 induces duplication of the embryonic axis (6,12).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive bioinformatic analysis of Wnt1 and Wnt1-associated diseases

Peng

Ren

et al. 2020

IRDR

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“…Furthermore, in vitro Rac1 seems to mediate wnt signal effects [24]. Since intermittent parathyroid hormone stimulates bone formation and a major pathway for bone formation is driven by wnt signaling we hypothesized that the deletion of Rac1 in preosteoblasts will prevent the increase in bone formation in response to PTH [16,27].…”

Section: Deletion Of Rac1 In Preosteoblasts Does Not Prevent the Respmentioning

confidence: 99%

“…The canonical wnt signaling pathway has also been studied [16], Indeed, studies on the canonical wnt signaling sclerostin led to the development of a therapeutic agent directed against the inhibitor sclerostin for the treatment of osteoporosis that was recently approved for use in patients in the US [17].…”

Section: Introductionmentioning

confidence: 99%

The Rho GTPase RAC1 in Osteoblasts Controls Their Function

Huck

Sens

Wuerfel

et al. 2020

IJMS

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The regulation of the differentiation of the bone-forming cells, the osteoblasts, is complex. Many signaling pathways converge on the master regulator of osteoblast differentiation Runx2. The role of molecules that integrate several signaling pathways such as the Rho GTPases need to be better understood. We, therefore, asked at which stage Rac1, one of the Rho GTPase, is needed for osteoblast differentiation and whether it is involved in two pathways, the anabolic response to parathyroid hormone and the stimulatory effect of fibronectin isoforms on integrins. Genetic deletion of Rac1 in preosteoblasts using the osterix promoter diminished osteoblast differentiation in vitro. This effect was however similar to the presence of the promoter by itself. We, therefore, applied a Rac1 inhibitor and confirmed a decrease in differentiation. In vivo, Rac1 deletion using the osterix promoter decreased bone mineral density as well as histomorphometric measures of osteoblast function. In contrast, deleting Rac1 in differentiating osteoblasts using the collagen α1(I) promoter had no effects. We then evaluated whether intermittent parathyroid hormone (PTH) was able to affect bone mineral density in the absence of Rac1 in preosteoblasts. The increase in bone mineral density was similar in control animals and in mice in which Rac1 was deleted using the osterix promoter. Furthermore, stimulation of integrin by integrin isoforms was able to enhance osteoblast differentiation, despite the deletion of Rac1. In summary, Rac1 in preosteoblasts is required for normal osteoblast function and bone density, but it is neither needed for PTH-mediated anabolic effects nor for integrin-mediated enhancement of differentiation.

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“…(22) Meanwhile, it was reported that inactivation of Wnt1 in osteoblast lineage cells causes low bone mass with accompanying fractures, and we could additionally demonstrate that inducible Wnt1 expression in osteoblasts causes a rapid osteoanabolic response, which does not require Lrp5. (23–25)…”

Section: Introductionmentioning

confidence: 99%

Mice Carrying a Ubiquitous R235W Mutation of Wnt1 Display a Bone-Specific Phenotype

Yorgan

Rolvien

Stürznickel

et al. 2020

Journal of Bone and Mineral Research

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Since a key function of Wnt1 in brain development was established early on through the generation of non‐viable Wnt1‐deficient mice, it was initially surprising that WNT1 mutations were found to cause either early‐onset osteoporosis (EOOP) or osteogenesis imperfecta type XV (OI‐XV). The deduced function of Wnt1 as an osteoanabolic factor has been confirmed in various mouse models with bone‐specific inactivation or overexpression, but mice carrying disease‐causing Wnt1 mutations have not yet been described. Triggered by the clinical analysis of EOOP patients carrying a heterozygous WNT1 mutation (p.R235W), we introduced this mutation into the murine Wnt1 gene to address the question of whether this would cause a skeletal phenotype. We observed that Wnt1+/R235W and Wnt1R235W/R235W mice were born at the expected Mendelian ratio and that they did not display postnatal lethality or obvious nonskeletal phenotypes. At 12 weeks of age, the homozygous presence of the Wnt1 mutation was associated with reduced trabecular and cortical bone mass, explained by a lower bone formation rate compared with wild‐type littermates. At 52 weeks of age, we also observed a moderate bone mass reduction in heterozygous Wnt1+/R235W mice, thereby underscoring their value as a model of WNT1‐dependent EOOP. Importantly, when we treated wild‐type and Wnt1+/R235W mice by daily injection of parathyroid hormone (PTH), we detected the same osteoanabolic influence in both groups, together with an increased cortical thickness in the mutant mice. Our data demonstrate the pathogenicity of the WNT1‐R235W mutation, confirm that controlling skeletal integrity is the primary physiological function of Wnt1, and suggest that osteoanabolic treatment with teriparatide should be applicable for individuals with WNT1‐dependent EOOP. © 2020 American Society for Bone and Mineral Research.

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Mesenchymal Cell-Derived Juxtacrine Wnt1 Signaling Regulates Osteoblast Activity and Osteoclast Differentiation

Cited by 37 publications

References 47 publications

Comprehensive bioinformatic analysis of Wnt1 and Wnt1-associated diseases

Comprehensive bioinformatic analysis of Wnt1 and Wnt1-associated diseases

The Rho GTPase RAC1 in Osteoblasts Controls Their Function

Mice Carrying a Ubiquitous R235W Mutation of Wnt1 Display a Bone-Specific Phenotype

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