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The role of CDK8 in mesenchymal stem cells in controlling osteoclastogenesis and bone homeostasis.

ABSTRACT: Bone marrow mesenchymal stem cells (MSCs) are critical regulators of postnatal bone homeostasis. Osteoporosis is characterized by bone volume and strength deterioration, partly due to MSC dysfunction. Cyclin-dependent kinase 8 (CDK8) belongs to the transcription-related CDK family. Here, CDK8 in MSCs was identified as important for bone homeostasis. CDK8 level was increased in aged MSCs along with the association with aging-related signals. Mouse genetic studies revealed that CDK8 in MSCs plays a crucial role in bone resorption and homeostasis. Mechanistically, CDK8 in MSCs extrinsically controls osteoclastogenesis through the signal transducer and transcription 1 (STAT1)-receptor activator of the nuclear factor κ Β ligand (RANKL) axis. Moreover, aged MSCs have high osteoclastogenesis-supporting activity, partly through a CDK8-dependent manner. Finally, pharmacological inhibition of CDK8 effectively repressed MSC-dependent osteoclastogenesis and prevented ovariectomy-induced osteoclastic activation and bone loss. These findings highlight that the CDK8-STAT1-RANKL axis in MSCs could play a crucial role in bone resorption and homeostasis.

SUBMITTER: Yamada T

PROVIDER: S-EPMC9287674 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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The role of CDK8 in mesenchymal stem cells in controlling osteoclastogenesis and bone homeostasis.

Yamada Takanori T Fukasawa Kazuya K Horie Tetsuhiro T Kadota Takuya T Lyu Jiajun J Tokumura Kazuya K Ochiai Shinsuke S Iwahashi Sayuki S Suzuki Akane A Park Gyujin G Ueda Rie R Yamamoto Megumi M Kitao Tatsuya T Shirahase Hiroaki H Ochi Hiroki H Sato Shingo S Iezaki Takashi T Hinoi Eiichi E

Stem cell reports 20220630 7

Bone marrow mesenchymal stem cells (MSCs) are critical regulators of postnatal bone homeostasis. Osteoporosis is characterized by bone volume and strength deterioration, partly due to MSC dysfunction. Cyclin-dependent kinase 8 (CDK8) belongs to the transcription-related CDK family. Here, CDK8 in MSCs was identified as important for bone homeostasis. CDK8 level was increased in aged MSCs along with the association with aging-related signals. Mouse genetic studies revealed that CDK8 in MSCs plays ...[more]

PMID: 35777359

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Project description:BackgroundSkeletal unloading usually induces severe disuse osteoporosis (DOP), which often occurs in patients subjected to prolonged immobility or in spaceflight astronauts. Increasing evidence suggests that exosomes are important mediators in maintaining the balance between bone formation and resorption. We hypothesized that exosomes play an important role in the maintenance of bone homeostasis through intercellular communication between bone marrow mesenchymal stem cells (BMSCs) and osteoclasts under mechanical loading.MethodsCells were divided into cyclic mechanical stretch (CMS)-treated BMSCs and normal static-cultured BMSCs, and exosomes were extracted by ultracentrifugation. After incubation with CMS-treated BMSC-derived exosomes (CMS_Exos) or static-cultured BMSC-derived exosomes (static_Exos), the apoptosis rates of bone marrow macrophages (BMMs) were determined by flow cytometry, and cell viability was detected with a Cell Counting Kit-8 (CCK-8) assay. Osteoclast differentiation was determined with an in vitro osteoclastogenesis assay. Signaling pathway activation was evaluated by western blotting and immunofluorescence staining. Hindlimb unloading (HU)-induced DOP mouse models were prepared to evaluate the function of exosomes in DOP.ResultsBoth CMS_Exos and static_Exos could be internalized by BMMs, and CMS_Exos did not affect BMM viability or increase apoptosis. The CMS_Exos effectively suppressed receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis and F-actin ring formation. Further molecular investigation demonstrated that CMS_Exos impaired osteoclast differentiation via inhibition of the RANKL-induced nuclear factor kappa-B (NF-κB) signaling pathway. Both CMS_Exos and static_Exos partly rescued the osteoporosis caused by mechanical unloading; however, the CMS_Exo group showed more obvious rescue. Treatment with CMS_Exos significantly decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts. Exosomes derived from CMS-treated BMSCs strongly inhibited osteoclast differentiation by attenuating the NF-κB signaling pathway in vitro and rescued osteoporosis caused by mechanical unloading in an HU mouse model in vivo.ConclusionsIn this research, we demonstrated that Exosomes derived from CMS-treated BMSCs inhibited osteoclastogenesis by attenuating NF-κB signaling pathway activity in vitro and ameliorated bone loss caused by mechanical unloading in an HU mouse model, providing new insights into intercellular communication between osteoblasts and osteoclasts under mechanical loading.

Dataset Information

The role of CDK8 in mesenchymal stem cells in controlling osteoclastogenesis and bone homeostasis.

Publications

The role of CDK8 in mesenchymal stem cells in controlling osteoclastogenesis and bone homeostasis.

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