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

• DOI: 10.1016/j.stemcr.2022.06.001
• Publication Date: 2022-06-30T17:09:31Z
• Authors: Takanori Yamada; Kazuya Fukasawa; Tetsuhiro Horie; Takuya Kadota; Jiajun Lyu; Kazuya Tokumura; Shinsuke Ochiai; Sayuki Iwahashi; Akane Suzuki; Gyujin Park; Rie Ueda; Megumi Yamamoto; Tatsuya Kitao; Hiroaki Shirahase; Hiroki Ochi; Shingo Sato; Takashi Iezaki; Eiichi Hinoi
• Keywords: 0301 basic medicine; RANK Ligand; NF-kappa B; Osteoclasts; Cell Differentiation; Mesenchymal Stem Cells; Cyclin-Dependent Kinase 8; Article; Mice; 03 medical and health sciences; Osteogenesis; Animals; Homeostasis; Female; Bone Resorption

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.