Smad1/5 and Smad4 Expression Are Important for Osteoclast Differentiation

Tasca, Amy; Stemig, Melissa; Broege, Aaron; Huang, Brandon; Davydova, Julia; Zwijsen, An; Umans, Lieve; Jensen, Eric D.; Gopalakrishnan, Rajaram; Mansky, Kim C.

doi:10.1002/jcb.25092

Cited by 23 publications

(40 citation statements)

References 25 publications

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“…106 Compared with control, Ad-CRE cells exhibited decreased osteoclast differentiation, as indicated by the presence of fewer and smaller multinuclear cells. 106 Moreover, expression of osteoclast-enriched genes Dc-stamp and Cathepsin K was reduced in Ad-CRE cells. 106 To further assess the effect of BMP-2 on osteoclast activity, mature osteoclasts were treated with either BMP-2 or dorsomorphin, a BMP pathway inhibitor.…”

Section: Osteoclast Activationmentioning

confidence: 93%

“…106 Moreover, expression of osteoclast-enriched genes Dc-stamp and Cathepsin K was reduced in Ad-CRE cells. 106 To further assess the effect of BMP-2 on osteoclast activity, mature osteoclasts were treated with either BMP-2 or dorsomorphin, a BMP pathway inhibitor. 106 Whereas BMP-2 stimulated osteoclast resorption, dorsomorphin blocked this activity.…”

Section: Osteoclast Activationmentioning

confidence: 97%

“…106 Specifically, loss of Smad1/5 or Smad4 expression was induced in osteoclasts precursors through infection with adenoviruses expressing Cre recombinase (Ad-CRE). 106 Compared with control, Ad-CRE cells exhibited decreased osteoclast differentiation, as indicated by the presence of fewer and smaller multinuclear cells. 106 Moreover, expression of osteoclast-enriched genes Dc-stamp and Cathepsin K was reduced in Ad-CRE cells.…”

Section: Osteoclast Activationmentioning

confidence: 99%

“…106 To further assess the effect of BMP-2 on osteoclast activity, mature osteoclasts were treated with either BMP-2 or dorsomorphin, a BMP pathway inhibitor. 106 Whereas BMP-2 stimulated osteoclast resorption, dorsomorphin blocked this activity. 106 Thus, both BMP-2 and elements of the canonical BMP pathway, including Smad1/5 and Smad4, are crucial to osteoclast differentiation and osteoclast-mediated resorption.…”

Section: Osteoclast Activationmentioning

confidence: 99%

“…106 Whereas BMP-2 stimulated osteoclast resorption, dorsomorphin blocked this activity. 106 Thus, both BMP-2 and elements of the canonical BMP pathway, including Smad1/5 and Smad4, are crucial to osteoclast differentiation and osteoclast-mediated resorption.…”

Section: Osteoclast Activationmentioning

confidence: 99%

See 4 more Smart Citations

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

James

LaChaud

Shen

et al. 2016

Tissue Engineering Part B: Reviews

821

769

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Bone morphogenetic protein-2 (BMP-2) is currently the only Food and Drug Administration (FDA)-approved osteoinductive growth factor used as a bone graft substitute. However, with increasing clinical use of BMP-2, a growing and well-documented side effect profile has emerged. This includes postoperative inflammation and associated adverse effects, ectopic bone formation, osteoclast-mediated bone resorption, and inappropriate adipogenesis. Several large-scale studies have confirmed the relative frequency of adverse events associated with the clinical use of BMP-2, including life-threatening cervical spine swelling. In fact, the FDA has issued a warning of the potential life-threatening complications of BMP-2. This review summarizes the known adverse effects of BMP-2, including controversial areas such as tumorigenesis. Next, select animal models that replicate BMP-2's adverse clinical effects are discussed. Finally, potential molecules to mitigate the adverse effects of BMP-2 are reviewed. In summary, BMP-2 is a potent osteoinductive cytokine that has indeed revolutionized the bone graft substitute market; however, it simultaneously has accrued a worrisome side effect profile. Better understanding of these adverse effects among both translational scientists and clinicians will help determine the most appropriate and safe use of BMP-2 in the clinical setting.

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Section: Osteoclast Activationmentioning

confidence: 93%

Section: Osteoclast Activationmentioning

confidence: 97%

Section: Osteoclast Activationmentioning

confidence: 99%

Section: Osteoclast Activationmentioning

confidence: 99%

Section: Osteoclast Activationmentioning

confidence: 99%

See 3 more Smart Citations

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

James

LaChaud

Shen

et al. 2016

Tissue Engineering Part B: Reviews

821

769

View full text Add to dashboard Cite

show abstract

Molecular Genetics of M yhre Syndrome

Michot

Goff

Cormier‐Daire

2016

Encyclopedia of Life Sciences

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Myhre syndrome (MIM 139210) is a rare autosomal‐dominant disorder characterised by short stature, brachydactyly, facial dysmorphism (short palpebral fissures, prognathism and short philtrum), developmental delay with mental retardation or/and behavioural troubles, progressive deafness of mixed conductive and sensory type and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility. Life‐threatening complications (obesity, arterial hypertension and bronchopulmonary insufficiency) are observed in the course of the disease leading to an early death. In 2011, SMAD4 (SMAD family member 4) has been identified as the disease‐causing gene. All mutations identified so far are de novo heterozygous missense mutations, mainly involving Ile500. While SMAD4 inactivation is reported in juvenile polyposis syndrome with increased colorectal cancer risk, no increased tumoural risk has been observed in Myhre syndrome. SMAD4 is a key mediator of TGF‐β (transforming growth factor beta)/BMP (bone morphogenetic protein) signalling and the understanding of the consequences of SMAD4 mutations during development will decipher new regulatory network related to TGF‐β/BMP signalling. Key Concepts Myhre syndrome is a rare genetic condition of autosomal‐dominant inheritance due to SMAD4 mutations affecting Arg496 or Ile500 residues. Myhre syndrome is characterised by short stature, brachydactyly, facial dysmorphism, developmental delay, progressive deafness and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility. Myhre syndrome is associated to a risk of early death due to possibly life‐threatening health conditions (obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis and pericarditis). Similar to mothers against decapentaplegic family member 4 ( SMAD4 ) encodes the common partner SMAD of the eight‐member family of SMAD proteins. SMAD4 aggregates into heterotrimer with the receptor‐regulated SMADs (R‐SMADs) once they are activated by phosphorylation by transmembrane serine–threonine receptor kinases in response to stimulation of TGF‐β, activin or BMP receptor pathways. The SMAD4 mutations identified in Myhre syndrome are expected to disturb the monoubiquitination of SMAD4 which occurs at Lys519 and also to disturb the function of the SMAD heterotrimer which regulates the expression of target genes. Germline heterozygous mutations in SMAD4 are known to cause juvenile polyposis syndrome (JPS) and JPS‐hereditary hemorrhagic telangiectasia. The SMAD4 mutations observed in JPS and JPS‐HHT include nonsense, missense, splice‐site changes and deletions, consistent with a loss‐of‐function mechanism. Increased tumoural risk has not been observed so far in Myhre syndrome. The development of tissue‐specific mouse models of Smad4 deficiency further highlighted the important role of Smad4 in a wide range of embryonic developmental processes.

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miR‐203a‐3p promotes loureirin A‐induced hair follicle stem cells differentiation by targeting Smad1

Luo

Dou

Xie

et al. 2020

The Anatomical Record

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MicroRNAs (miRNAs) participate in the repair of skin trauma. Our previous study indicated that loureirin A promoted hair follicle stem cells (HFSCs) to repair skin epidermis. However, the mechanism of miRNA‐mediated regulation of loureirin A‐induced HFSC differentiation remained to be explored. In the present study, HFSCs from rat vibrissa were identified by immunofluorescence in vitro. Microarray and quantitative real time polymerase chain reaction analyses demonstrated that miR‐203a‐3p was upregulated in differentiated HFSCs induced by loureirin A. The expression of cytoskeletal keratin (CK) 5 and involucrin was promoted by miR‐203a‐3p mimics while repressed by a miR‐203a‐3p inhibitor. Smad1 was identified as a key target of miR‐203a‐3p using target prediction tools. Luciferase reporter gene test confirmed a special target association between miR‐203a‐3p and Smad1. Short interfering Smad1 was transfected into HFSCs, and the expression levels of CK5 and involucrin were upregulated. Thus, it can be inferred that miR‐203a‐3p negatively regulated the expression of Smad1 and promoted the differentiation of loureirin A‐induced HFSCs. Bone morphogenetic protein (BMP) signal inhibition and Wnt activation coregulate skin injury repair. BMP/Smad1 signaling is involved in maintaining the characteristics of HFSCs and inhibiting their differentiation. Our results showed that miR‐203a‐3p reduces Smad1 to release BMP inhibition. Taken together, miR‐203a‐3p/Smad1 is a potential therapeutic molecular target in skin wound healing, and may play an active role in wound repair and regenerative medicine.

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Smad1/5 and Smad4 Expression Are Important for Osteoclast Differentiation

Cited by 23 publications

References 25 publications

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

Molecular Genetics of M yhre Syndrome

miR‐203a‐3p promotes loureirin A‐induced hair follicle stem cells differentiation by targeting Smad1

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