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Osteoclast role in Haemophilic Bone disease

1Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Rome, Lazio, Italy, 2Bone Physiopathology Group, Multifactorial Disease and Complex Phenotype Research Area, Bambino Gesù Children’s Hospital, Rome, Lazio, Italy, 3Catholic University of Sacred Heart, Translational Medicine and Surgery Department, Rome, Lazio, Italy, 4Fondazione Policlinico Universitario A. Gemelli, IRCCS, Center for Hemorrhagic and Thrombotic Diseases and Haemophilia Center, Rome, Rome, Lazio, Italy

Abstract Number: OC 20.3

Meeting: ISTH 2022 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Basic

Background: Bone disease is a significant complication of haemophilia A (HA), but its pathogenesis still remains unknown. The reduction of bone mineral density seems due to perturbations of the Receptor Activator of Nuclear factor-B RANK Ligand (RANKL) and osteoprotegerin (OPG) pathways. In haemophilic alterations of bone remodeling, osteoclasts seem to play an important role. Osteoclasts are multinucleated cells which derived from the CD14+ monocyte/macrophage lineage. Until recently, the identity of osteoclast progenitors has not been well defined, but evidences report that CD16−CD14+ rather than CD16+CD14+ monocytes were prone to differentiate into osteoclasts [1].

Aims: This study aims to evaluate whether the osteoclastogenesis could be influenced by the FVIII, von Willebrand Factor (VWF) and thrombin and to assess the osteoclastogenic potential from two different HA patients.

Methods: Osteoclastogenesis of healthy donors-derived PBMC (Peripheral Blood Mononuclear Cells) were assessed in the presence of plasma derived VWF/FVIII complex, rVWF, rFVIII and thrombin. FACS-analysis, in vitro assays and gene expression analysis were performed to evaluate osteoclast precursors and osteoclastogenic potential of PBMC isolated from two haemophilic patients.

Results: VWF appears to play a major role to regulate osteoclast differentation from healthy donor-derived PBMC. Indeed, it inhibits by itself ~45% the osteoclastogenesis comparable to OPG, and even more if is complexed with FVIII (53%inhibition). Thrombin reduces osteoclast differentiation with variable effects (30-50% inhibition).

PBMC from HA patients showed increased ability to form mature osteoclasts compared to those obtained from healthy controls. Osteoclast precursors (CD16−CD14+CD11b+) are significantly higher in HA patients than age and sex matched controls (~33%). Moreover, RNA expression analysis performed on patient’s osteoclasts revealed higher levels of RANK, TRAF6, CATHEPSIN-K and TCIRG1 genes expression compared to matched controls.

Conclusion(s): All these data support that bone loss observed in haemophilic patients could be related to increased osteoclast formation and activity and that coagulation factors directly impact on bone cells.

To cite this abstract in AMA style:

Lancellotti S, Battafarano G, Sacco M, Tardugno M, Di Gennaro L, De Cristofaro R, Del Fattore A. Osteoclast role in Haemophilic Bone disease [abstract]. https://abstracts.isth.org/abstract/osteoclast-role-in-haemophilic-bone-disease/. Accessed October 1, 2023.

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