Melanoma bone metastasis-induced osteocyte ferroptosis via the HIF1α-HMOX1 axis.

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Abstract

[Indexed for MEDLINE] Conflict of interest statement: Competing interests: The authors declare no competing interests. 8. Exp Hematol Oncol. 2025 Aug 22;14(1):108. doi: 10.1186/s40164-025-00699-4. Healing of lytic lesions and restoration of bone health in multiple myeloma through sclerostin inhibition. Sabol HM(1), Anloague A(1), Kaur J(1)(2), Bustamante-Gomez C(3), Khan S(1), Paxton BC(1), Nester MR(1), Hackney J(1), Diaz-delCastillo M(4), Mann D(5), Stambough JB(6), Barnes CL(6), Ambrogini E(3)(7)(8), Frontier A(9), Ebetino FH(9)(10), Naqvi S(11), van Rhee F(2)(11), Wardell CP(5)(7), Drake MT(12), Nookaew I(1)(2)(5)(7), Schinke C(2)(11), Zangari M(2)(11), Delgado-Calle J(13)(14)(15)(16). Author information: (1)Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR, USA. (2)Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA. (3)Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA. (4)Forensic Medicine, University of Aarhus, Aarhus, Denmark. (5)Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. (6)Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA. (7)Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences, Little Rock, AR, USA. (8)Central Arkansas Veterans Healthcare System, Little Rock, AR, USA. (9)Department of Chemistry, University of Rochester, Rochester, NY, USA. (10)Biovinc LLC, Pasadena, CA, USA. (11)Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA. (12)Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA. (13)Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR, USA. jdelgadocalle@uams.edu. (14)Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA. jdelgadocalle@uams.edu. (15)Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA. jdelgadocalle@uams.edu. (16)Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences, Little Rock, AR, USA. jdelgadocalle@uams.edu. BACKGROUND: Multiple myeloma (MM) is associated with a debilitating bone disease that poses significant therapeutic challenges. MM bone disease is characterized by increased bone resorption and suppression of osteoblasts, which hinders the repair of damaged bone. Sclerostin, an antagonist of Wnt signaling, is elevated in MM patients, and its inhibition with a neutralizing antibody (Scl-ab) has been shown to restore osteoblast function in mouse models of MM. However, it remains unclear whether Scl-ab can promote skeletal repair, enable effective tumor control when combined with anti-cancer agents, or improve bone health in MM patients. METHODS: To investigate these knowledge gaps, we used preclinical MM mouse models and patient-derived samples. We also characterize the impact of Scl-ab on cancer and osteoblastic cells isolated from mouse models through bulk and single-cell RNA sequencing. Lastly, we performed a retrospective analysis of the efficacy of Scl-ab to improve bone health in patients with MM in remission. RESULTS: Scl-ab promoted skeletal repair and enabled tumor suppression by an anti-cancer agent in various animal models of established MM bone disease. MM tumors suppressed Wnt signaling and decreased the number of osteoblasts and osteo-CAR cells, and treatment with Scl-ab reversed these effects. Treatment with Scl-ab increased bone mass and repaired bone in patients with MM in remission, even when combined with maintenance chemotherapy. CONCLUSIONS: Our findings highlight the potent bone-healing effects of Scl-ab and its potential as an adjuvant to anti-cancer therapy, offering a promising approach to improve clinical outcomes and the quality of life for MM patients. © 2025. The Author(s). DOI: 10.1186/s40164-025-00699-4 PMCID: PMC12372396