Academic Journal
Pharmacological inhibition of Htr2b ameliorates bone destruction in glucocorticoid-induced osteonecrosis of the femoral head by suppressing Ca2+/ERK ‑ dependent osteoclast hyperactivation.
| Τίτλος: | Pharmacological inhibition of Htr2b ameliorates bone destruction in glucocorticoid-induced osteonecrosis of the femoral head by suppressing Ca2+/ERK ‑ dependent osteoclast hyperactivation. |
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| Συγγραφείς: | Yuan T; Department of Joint Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Wang Y; Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Skeletal Aging Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China., Qin C; Department of Joint Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Qian K; Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Skeletal Aging Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China., Lv Y; Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Skeletal Aging Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China., Wang W; Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Skeletal Aging Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China., Li Z; Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Skeletal Aging Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China. Electronic address: liziqing@sdfmu.edu.cn., Sun S; Department of Joint Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Skeletal Aging Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China. Electronic address: sunshui@sdfmu.edu.cn. |
| Πηγή: | Biochemical pharmacology [Biochem Pharmacol] 2026 Sep; Vol. 251 (Pt 1), pp. 118120. Date of Electronic Publication: 2026 Jun 03. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Oxford : Elsevier Science Original Publication: Oxford, New York [etc.] Paragamon Press. |
| Ιατρικοί όροι (MeSH): | Osteoclasts*/drug effects , Osteoclasts*/metabolism , Receptor, Serotonin, 5-HT2B*/metabolism , Receptor, Serotonin, 5-HT2B*/genetics , Glucocorticoids*/toxicity , Serotonin 5-HT2 Receptor Antagonists*/pharmacology , Serotonin 5-HT2 Receptor Antagonists*/therapeutic use , Femur Head Necrosis*/chemically induced , Femur Head Necrosis*/metabolism , Femur Head Necrosis*/drug therapy , Femur Head Necrosis*/pathology , Calcium*/metabolism , MAP Kinase Signaling System*/drug effects , MAP Kinase Signaling System*/physiology, Dexamethasone/toxicity ; Femur Head/drug effects ; Femur Head/metabolism ; Femur Head/pathology ; Animals ; Mice, Inbred C57BL ; Mice ; Male |
| Περίληψη: | Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a progressive and disabling disease caused by the prolonged use of glucocorticoids. Accumulating evidence has established an association between hyperactivated osteoclasts and pathological bone erosion in GIONFH. Expression of 5-hydroxytryptamine receptor 2b (Htr2b), a canonical serotonin receptor, is upregulated during osteoclast maturation. Nevertheless, the underlying mechanisms governing this phenomenon, especially in relation to GIONFH, remain unexplored. In this study, the expression of Htr2b in osteoclast precursor cells (OPCs) treated with dexamethasone (DEX) was assessed using RNA sequencing. Functional validation was subsequently performed through siRNA-mediated knockdown and RS-127445-mediated pharmacological inhibition of Htr2b. Based on the developmental physiological features of the murine femoral head, we developed an innovative GIONFH model using six-month-old C57BL/6J mice and subjected them to an RS-127445 therapeutic intervention. RNA sequencing revealed significant upregulation of Htr2b expression in DEX-stimulated hyperactive osteoclasts. In vitro results demonstrated that Htr2b inhibition impeded osteoclast hyperactivation under DEX stimulation by suppressing nuclear factor of activated T cells 1 (Nfatc1) expression and nuclear translocation. At the mechanistic level, Htr2b inhibition interfered with calcium oscillation and ERK1/2 phosphorylation, thereby ceasing osteoclastogenesis. In vivo, integrated micro-CT and histomorphometry analyses revealed that RS-127445 (10 mg/kg) rescued methylprednisolone (MPS)-induced bone destruction and vascular damage in the femoral head by inhibiting osteoclast activity and promoting vascular formation. Our findings highlight the positive role of Htr2b in osteoclastogenesis exposed to glucocorticoids, suggesting that Htr2b is a novel therapeutic target for early pathological changes of GIONFH. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of Competing Interest The authors have declared that no competing interests exist. |
| Contributed Indexing: | Keywords: Calcium oscillation; Glucocorticoid; Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH); Htr2b; Nfatc1; Osteoclast |
| Substance Nomenclature: | 0 (Receptor, Serotonin, 5-HT2B) 0 (Glucocorticoids) 7S5I7G3JQL (Dexamethasone) 0 (Serotonin 5-HT2 Receptor Antagonists) SY7Q814VUP (Calcium) |
| Entry Date(s): | Date Created: 20260604 Date Completed: 20260712 Latest Revision: 20260712 |
| Update Code: | 20260713 |
| DOI: | 10.1016/j.bcp.2026.118120 |
| PMID: | 42242505 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1873-2968 |
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| DOI: | 10.1016/j.bcp.2026.118120 |