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IgSF11-mediated phosphorylation of pyruvate kinase M2 regulates osteoclast differentiation and prevents pathological bone loss

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Bone Research 2023年第1期11卷 215-227页

作者： Hyunsoo Kim Noriko Takegahara yongwon choi Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of MedicinePhiladelphiaPA19104USA

Osteoclasts are primary bone-resorbing cells,and receptor-activated NF-k B ligand(RANKL)stimulation is the key driver of osteoclast *** late-stage differentiation,osteoclasts become multinucleated and enlarged(so-called“maturation”),suggesting their need to adapt to changing metabolic demands and a substantial increase in ***,we demonstrate that immunoglobulin superfamily 11(Ig SF11),which is required for osteoclast differentiation through an association with the postsynaptic scaffolding protein PSD-95,regulates osteoclast differentiation by controlling the activity of pyruvate kinase M isoform2(PKM2).By using a system that directly induces the activation of Ig SF11 in a controlled manner,we identified PKM2 as a major Ig SF11-induced tyrosine-phosphorylated *** SF11 activates multiple Src family tyrosine kinases(SFKs),including c-Src,Fyn,and Hc K,which phosphorylate PKM2 and thereby inhibit PKM2 ***,Ig SF11-deficient cells show higher PKM2activity and defective osteoclast ***,inhibiting PKM2 activities with the specific inhibitor Shikonin rescues the impaired osteoclast differentiation in Ig SF11-deficient cells,and activating PKM2 with the specific activator TEPP46 suppresses osteoclast differentiation in wild-type ***,PKM2 activation further suppresses osteoclastic bone loss without affecting bone formation in *** together,these results show that Ig SF11 controls osteoclast differentiation through PKM2 activity,which is a metabolic switch necessary for optimal osteoclast maturation.

关键词： SF11 osteoclast impaired

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Ig SF11 regulates osteoclast differentiation through association with the scaffold protein PSD-95

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Bone Research 2020年第1期8卷 97-106页

作者： Hyunsoo Kim Noriko Takegahara Matthew CWalsh Sarah AMiddleton Jiyeon Yu Jumpei Shirakawa Jun Ueda Yoshitaka Fujihara Masahito Ikawa Masaru Ishii Junhyong Kim yongwon choi Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of MedicinePhiladelphiaPA 19104USA Department of Biology Department of Computer and Information ScienceSchool of Arts and SciencesProgram in Single Cell BiologyUniversity of PennsylvaniaPhiladelphiaPA 19104USA Research Institute for Microbial Diseases Osaka UniversitySuitaOsaka 565-0871Japan Department of Immunology and Cell Biology Graduate School of Medicine and Frontier BiosciencesOsaka UniversitySuitaOsaka 565-0871Japan

Osteoclasts are multinucleated, giant cells derived from myeloid progenitors. While receptor activator of NF-κB ligand(RANKL)stimulation is the primary driver of osteoclast differentiation, additional signaling further contributes to osteoclast ***, we demonstrate that immunoglobulin superfamily member 11(Ig SF11), whose expression increases during osteoclast differentiation, regulates osteoclast differentiation through interaction with postsynaptic density protein 95(PSD-95), a scaffold protein with multiple protein interaction domains. Ig SF11 deficiency in vivo results in impaired osteoclast differentiation and bone resorption but no observed defect in bone formation. Consequently, Ig SF11-deficient mice exhibit increased bone *** in vitro osteoclast culture systems, we show that Ig SF11 functions through homophilic interactions. Additionally, we demonstrate that impaired osteoclast differentiation in Ig SF11-deficient cells is rescued by full-length Ig SF11 and that the Ig SF11-PSD-95 interaction requires the 75 C-terminal amino acids of Ig SF11. Our findings reveal a critical role for Ig SF11 during osteoclast differentiation and suggest a role for Ig SF11 in a receptor-and signal transduction molecule-containing protein complex.

关键词： SF11 osteoclast impaired

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