Regulation of Osteoclast Differentiation at Multiple Stages by Protein Kinase D Family Kinases

Leightner, Amanda C.; Meyers, Carina Mello Guimaraes; Evans, Michael D.; Mansky, Kim C.; Gopalakrishnan, Rajaram; Jensen, Eric D.

doi:10.3390/ijms21031056

Cited by 7 publications

(3 citation statements)

References 62 publications

(79 reference statements)

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“…A well-formed podosome actin belt was regarded as the mature osteoclast actin cytoskeleton, reflecting osteoclastic bone resorption capacity ( Leightner et al, 2020 ). Thus, immunofluorescence staining of mature osteoclasts was carried out to evaluate the impact of CD40L and TRAF-STOP on the function of the osteoclast ( Figures 3A, C ).…”

Section: Resultsmentioning

confidence: 99%

TRAF-STOP alleviates osteoclastogenesis in periodontitis

Huang

Zhan

et al. 2023

Front. Pharmacol.

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The enhanced osteoclastogenesis contributes to alveolar bone resorption in periodontitis, which increases the risk of tooth loss. To reduce bone destruction, the inhibition of osteoclast development is proposed as a feasible treatment. CD40L-CD40-TRAF6 signal transduction plays a crucial role in inflammation, but how it regulates osteoclast activity in periodontitis has not been elucidated. In this study, we showed the potential role of CD40L-CD40-TRAF6 signaling in periodontitis. CD40L obviously promoted osteoclast formation and bone resorption capacity in vitro. Mechanistically, we found that osteoclastogenesis was enhanced by the overexpression of NFATc1 and NF-κB activation. Importantly, osteoclast activity was effectively suppressed by TRAF-STOP, a small molecular inhibitor of TRAF6. Furthermore, local injection of TRAF-STOP-loaded injectable PLGA-PEG-PLGA hydrogel could alleviate ligation-induced periodontitis in vivo. Taken together, TRAF-STOP shows promising clinical efficacy in periodontitis through alleviating osteoclastogenesis.

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Section: Resultsmentioning

confidence: 99%

TRAF-STOP alleviates osteoclastogenesis in periodontitis

Huang

Zhan

et al. 2023

Front. Pharmacol.

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“…PKD plays an important role in osteoclast formation. Treatment of bone marrow macrophages with CRT0066101 or CID755673 prevents them from becoming osteoclasts, indicating the importance of PKD in bone health ( 68 ). In another study, CRT6600101 carried by nanomaterials reduced IL-1β-induced inflammatory stress in chondrocytes via the NF-κB pathway ( 69 ).…”

Section: Pkd Inhibitors As Effective Therapeutic Strategies Against Diseasementioning

confidence: 99%

Small-Molecule Inhibitor Targeting Protein Kinase D: A Potential Therapeutic Strategy

Chen

Feng

et al. 2021

Front. Oncol.

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The protein kinase D (PKD) family is a family of serine-threonine kinases that are members of the calcium/calmodulin-dependent kinase (CaMK) superfamily. PKDs have been increasingly implicated in multiple pivotal cellular processes and pathological conditions. PKD dysregulation is associated with several diseases, including cancer, inflammation, and obesity. Over the past few years, small-molecule inhibitors have emerged as alternative targeted therapy with fewer adverse side effects than currently available chemotherapy, and these specifically targeted inhibitors limit non-specific toxicities. The successful development of PKD inhibitors would significantly suppress the growth and proliferation of various cancers and inhibit the progression of other diseases. Various PKD inhibitors have been studied in the preclinical setting. In this context, we summarize the PKD inhibitors under investigation and their application for different kinds of diseases.

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“…In addition to the previously described pathways, other pathways in the regulation of osteoclastogenesis are being investigated. A new mechanism of osteoclast differentiation has been described and the role of protein kinase D from the kinase family in the regulation of osteoclast activity has been established (Leightner et al, 2020).…”

Section: Figmentioning

confidence: 99%

Bone remodeling stages under physiological conditions and glucocorticoid in excess: Focus on cellular and molecular mechanisms

Povoroznyuk

Dedukh

Bystrytska

et al. 2021

Regul. Mech. Biosyst.

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This review provides a rationale for the cellular and molecular mechanisms of bone remodeling stages under physiological conditions and glucocorticoids (GCs) in excess. Remodeling is a synchronous process involving bone resorption and formation, proceeding through stages of: (1) resting bone, (2) activation, (3) bone resorption, (4) reversal, (5) formation, (6) termination. Bone remodeling is strictly controlled by local and systemic regulatory signaling molecules. This review presents current data on the interaction of osteoclasts, osteoblasts and osteocytes in bone remodeling and defines the role of osteoprogenitor cells located above the resorption area in the form of canopies and populating resorption cavities. The signaling pathways of proliferation, differentiation, viability, and cell death during remodeling are presented. The study of signaling pathways is critical to understanding bone remodeling under normal and pathological conditions. The main signaling pathways that control bone resorption and formation are RANK / RANKL / OPG; M-CSF – c-FMS; canonical and non-canonical signaling pathways Wnt; Notch; MARK; TGFβ / SMAD; ephrinB1/ephrinB2 – EphB4, TNFα – TNFβ, and Bim – Bax/Bak. Cytokines, growth factors, prostaglandins, parathyroid hormone, vitamin D, calcitonin, and estrogens also act as regulators of bone remodeling. The role of non-encoding microRNAs and long RNAs in the process of bone cell differentiation has been established. MicroRNAs affect many target genes, have both a repressive effect on bone formation and activate osteoblast differentiation in different ways. Excess of glucocorticoids negatively affects all stages of bone remodeling, disrupts molecular signaling, induces apoptosis of osteocytes and osteoblasts in different ways, and increases the life cycle of osteoclasts. Glucocorticoids disrupt the reversal stage, which is critical for the subsequent stages of remodeling. Negative effects of GCs on signaling molecules of the canonical Wingless (WNT)/β-catenin pathway and other signaling pathways impair osteoblastogenesis. Under the influence of excess glucocorticoids biosynthesis of biologically active growth factors is reduced, which leads to a decrease in the expression by osteoblasts of molecules that form the osteoid. Glucocorticoids stimulate the expression of mineralization inhibitor proteins, osteoid mineralization is delayed, which is accompanied by increased local matrix demineralization. Although many signaling pathways involved in bone resorption and formation have been discovered and described, the temporal and spatial mechanisms of their sequential turn-on and turn-off in cell proliferation and differentiation require additional research.

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Regulation of Osteoclast Differentiation at Multiple Stages by Protein Kinase D Family Kinases

Cited by 7 publications

References 62 publications

TRAF-STOP alleviates osteoclastogenesis in periodontitis

TRAF-STOP alleviates osteoclastogenesis in periodontitis

Small-Molecule Inhibitor Targeting Protein Kinase D: A Potential Therapeutic Strategy

Bone remodeling stages under physiological conditions and glucocorticoid in excess: Focus on cellular and molecular mechanisms

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