Role of MKP-1 in Osteoclasts and Bone Homeostasis

Carlson, J.; Cui, Weiguo; Zhang, Qing; Xu, Xiaoqing; Mercan, Fatih; Bennett, Anton M.; Vignery, Agnès

doi:10.2353/ajpath.2009.090035

Cited by 34 publications

(40 citation statements)

References 30 publications

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“…Previous work by others has established that Dusp1 deficient mice have a smaller skeletal phenotype compared to matched WT littermates [37]. Interestingly, our group has also showed that deletion of Dusp-1 resulted in less OC as a result of reduced Vitamin D-induced RANKL expression in bone marrow stromal populations due to impaired RXR/VDR heterodimer nuclear translocation [38].…”

Section: Discussionmentioning

confidence: 64%

MKP-1 signaling events are required for early osteoclastogenesis in lineage defined progenitor populations by disrupting RANKL-induced NFATc1 nuclear translocation

Valerio

Herbert

Griffin

et al. 2014

Bone

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Cytokine-directed osteoclastogenesis is initiated in response to macrophage colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL), to drive formation of osteoclasts (OC), large bone resorptive cells of hematopoietic origin. RANKL-induced signaling activates the MAPK pathways, which initiates nuclear translocation of the master regulator of osteoclast formation, transcription factor NFATc1. Proper control over these signaling events is essential to normal OC formation response to stimuli. MAPK phosphatase 1 (MKP-1), a serine and tyrosine phosphatase encoded by the gene Dusp1, functions to dephosphorylate and subsequently inactivate MAPK (p38 and JNK) signaling essential in osteoclastogenesis. Here, we explored the role of MKP-1 during RANKL-driven osteoclastogenesis from defined (B220/CD45− GR1−CD11blo/−CD115+) OC progenitor (dOCP) populations using WT and Dusp1−/− global knockout mice. Sorted cells were driven to OC by M-CSF pre-treatment followed by RANKL stimulation for 3 days. OC formation and qPCR products were analyzed for maturation. Results indicate that Dusp1−/− dOCP form less numerous, significantly smaller and less functional OC compared to WT controls. These data were corroborated by mRNA expression of the key OC genes, Nfatc1 and Tm7sf4 (DC-STAMP), which were significantly reduced in early osteoclastogenesis in OC progenitor from Dusp1−/− mice. Intriguingly, our data reveals that MKP-1 may positively control OC formation in response to RANKL by regulating NFATc1 nuclear translocation. Collectively, this report supports the idea that MKP-1 signaling is essential in early osteoclastogenesis in response to RANKL-induced signaling.

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Section: Discussionmentioning

confidence: 64%

MKP-1 signaling events are required for early osteoclastogenesis in lineage defined progenitor populations by disrupting RANKL-induced NFATc1 nuclear translocation

Valerio

Herbert

Griffin

et al. 2014

Bone

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“…Our study emphasized the important role of MKP-1 in maintaining bone homeostasis, suggesting the potential therapeutic effects of MKP-1 gene transfer in diseases associated with inflammatory bone loss. A recent study showed that MKP-1 KO mice had equivalent bone loss, but fewer osteoclasts compared with WT mice after ovariectomy 34 . Instead they showed that osteoclasts from MKP-1 KO mice had higher resorptive activity than osteoclasts from WT mice.…”

Section: Discussionmentioning

confidence: 98%

Anti-inflammatory effect of MAPK phosphatase-1 local gene transfer in inflammatory bone loss

Herbert

et al. 2010

Gene Ther

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Alveolar bone loss associated with periodontal diseases is the result of osteoclastogenesis induced by bacterial pathogens. The mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP- 1) is a critical negative regulator of immune response as a key phosphatase capable of dephosphorylating activated MAPKs. In this study, rat macrophages transduced with recombinant adenovirus (Ad).MKP-1 specifically dephosphorylated activated MAPKs induced by lipopolysaccharide (LPS) compared with control cells. Bone marrow macrophages from MKP-1 knockout (KO) mice exhibited higher interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and select chemokine compared with wild type (WT) mice when stimulated by LPS. In addition, bone marrow cultures from MKP-1 KO mice exhibited significantly more osteoclastogenesis induced by LPS compared with WT mice. Importantly, MKP-1 gene transfer in bone marrow cells of MKP-1 KO mice significantly decreased IL-6, IL-10, TNF-α, chemokine levels and formed fewer osteoclasts induced by LPS compared with control group of cells. Furthermore, MKP-1 gene transfer in an experimental periodontal disease model attenuated bone resorption induced by LPS. Histological analysis confirmed that periodontal tissues transduced with Ad.MKP-1 exhibited less infiltrated inflammatory cells, less osteoclasts and less IL-6 compared with rats of control groups. These studies indicate that MKP-1 is a key therapeutic target to control of inflammation-induced bone loss.

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“…It is a negative regulator of innate and adaptative immunity, it plays an important role in metabolism, potentially a pathophysiological role in the progression of obesity and metabolic syndrome and is a regulator of bone mass as well [31], [44]. Actually, the lack of MKP-1 is associated with a reduced trabecular bone density in female mice [45], [46]. In vivo , Carlson et al demonstrated that MKP-1 negatively regulates osteoclast differentiation and activation in response to LPS injection.…”

Section: Discussionmentioning

confidence: 99%

The Polyphenol Fisetin Protects Bone by Repressing NF-κB and MKP-1-Dependent Signaling Pathways in Osteoclasts

et al. 2013

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Osteoporosis is a bone pathology leading to increase fractures risk and challenging quality of life. Since current treatments could exhibit deleterious side effects, the use of food compounds derived from plants represents a promising innovative alternative due to their potential therapeutic and preventive activities against human diseases. In this study, we investigated the ability of the polyphenol fisetin to counter osteoporosis and analyzed the cellular and molecular mechanisms involved. In vivo, fisetin consumption significantly prevented bone loss in estrogen deficiency and inflammation mice osteoporosis models. Indeed, bone mineral density, micro-architecture parameters and bone markers were positively modulated by fisetin. Consistent with in vivo results, we showed that fisetin represses RANKL-induced osteoclast differentiation and activity as demonstrated by an inhibition of multinucleated cells formation, TRAP activity and differentiation genes expression. The signaling pathways NF-κB, p38 MAPK, JNK and the key transcription factors c-Fos and NFATc1 expressions induced by RANKL, were negatively regulated by fisetin. We further showed that fisetin inhibits the constitutive proteasomal degradation of MKP-1, the phosphatase that deactivates p38 and JNK. Consistently, using shRNA stable cell lines, we demonstrated that impairment of MKP-1 decreases fisetin potency. Taken together, these results strongly support that fisetin should be further considered as a bone protective agent.

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Role of MKP-1 in Osteoclasts and Bone Homeostasis

Cited by 34 publications

References 30 publications

MKP-1 signaling events are required for early osteoclastogenesis in lineage defined progenitor populations by disrupting RANKL-induced NFATc1 nuclear translocation

MKP-1 signaling events are required for early osteoclastogenesis in lineage defined progenitor populations by disrupting RANKL-induced NFATc1 nuclear translocation

Anti-inflammatory effect of MAPK phosphatase-1 local gene transfer in inflammatory bone loss

The Polyphenol Fisetin Protects Bone by Repressing NF-κB and MKP-1-Dependent Signaling Pathways in Osteoclasts

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