Background: Indolent systemic mastocytosis (ISM) is a rare haematological condition defined by the proliferation and accumulation of abnormal clonal mast cells in extra-cutaneous organs. Osteoporosis (OP) is a common skeletal event in ISM, often resulting in multiple vertebral fractures (VF) [1]. The pathogenesis of OP in ISM is thought to be driven by mast cell-derived mediators, including interleukin-6 (IL-6), and activating KIT mutation, which disrupt bone remodelling and promote osteoclast-mediated bone resorption. Current risk assessment for OP and VF in ISM relies on conventional clinical, biological, and densitometric parameters used in other forms of OP, with no disease-specific biomarkers integrated into routine practice [2,3]. Given that key effector cells in ISM (mast cells) and OP (monocytes, osteoclasts, and potentially T lymphocytes) originate from bone marrow and circulate in peripheral blood, we hypothesize that molecular profiling of circulating leukocytes may reveal novel determinants of ISM-associated OP.

Objectives: To evaluate the pro-osteoporotic determinants in the blood compartment of ISM patients at both transcriptomic and protein level.

Methods: Patients and controls were recruited from the Mastocytosis National Expert Centre (CEREMAST, Toulouse). Peripheral blood samples were obtained at diagnosis, and fresh circulating leukocytes were isolated by centrifugation. Transcriptomic profiling was performed using single-cell RNA sequencing (scRNA-seq). Bioinformatic analyses focused on transcriptional pathways in circulating osteoclast precursors, namely monocytes. To delineate specific markers of ISM-associated OP, 4 groups of patients, each comprising four age- and gender-matched individuals, were compared: ISM with OP, ISM without OP, controls with OP, and controls without OP. In addition, to identify ISM-specific biomarkers associated with OP, serum levels of ten soluble mediators involved in bone remodelling (IL-6, IL-10, IL-17A, TNF, GM-CSF, M-CSF, RANKL, CXCL1, TIGIT, FGF-23) were quantified using Meso Scale Discovery U-plex®. This protein analysis included 14 ISM patients with OP to 26 controls with OP.

Results: Our scRNA-seq analysis revealed a distinct transcriptomic signature in blood monocytes from ISM patients with OP (Figure 1A-C ). Comparison of ISM patients with OP to controls identified 12 differentially expressed genes (DEGs). Pathway enrichment analysis demonstrated an upregulation of osteoclast differentiation (Reactome Pathways 2024 database) and IL-1 signalling (KEGG database) specifically in CD14+ monocytes, but not in the CD16+ monocytes subpopulation ( Figure 1A-B ). Venn diagram analysis further highlighted C3AR1 and IFITM3 as candidate biomarkers associated with OP in both CD14+ and CD16+ monocytes. The functional STRING network clustering showed the link of these markers with IL-1 signalling ( Figure 1C ). At the protein level, study of pre-selected 10 serum pro-osteoclastogenic soluble proteins did not discriminate ISM related OP from post-menopausal OP (Figure 1D-E ). However, these findings do not preclude a role for these mediators within the bone marrow microenvironment or the involvement of other circulating effectors.

Conclusions: Circulating monocytes of patients with osteoporosis related to systemic mastocytosis exhibit a distinct phenotypic profile characterized by an increased potential for osteoclastogenesis, mediated through activation of the IL-1 signalling pathway.

Figure 1.

REFERENCES: [1] Management of Bone Health in Adult Mastocytosis. Degboé Y. et al. , Curr Osteoporos Rep. 2025 Feb 13;23(1):10. doi: 10.1007/s11914-025-00901-w.

[2] Predictors of new fragility fractures after diagnosis of indolent systemic mastocytosis. Van der Veer E. et al. , J Allergy Clin Immunol. 2014 Dec;134(6):1413-1421. doi: 10.1016/j.jaci.2014.05.003.

[3] Prevalence and risk factors for fragility fracture in systemic mastocytosis. Degboé Y. et al. , Bone. 2017 Dec;105:219-225. doi: 10.1016/j.bone.2017.09.005.

Acknowledgments: NIL.

Disclosure of Interests: Yannick Degboé Blueprint medicines, Mélissa Galindo: None declared, Lilian Basso: None declared, Margot Zahm: None declared, Adeline Ruyssen-Witrand: None declared, Bénédicte Razat: None declared, Nicolas Gaudenzio: None declared, Cristina Bulai Livideanu: None declared.