Bone marrow transplantation improves autoinflammation and inflammatory bone loss in SH3BP2 knock-in cherubism mice

Abstract

Cherubism (OMIM#118400) is a genetic disorder in children characterized by excessive jawbone destruction with proliferation of fibro-osseous lesions containing a large number of osteoclasts. Mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for cherubism. Analysis of the knock-in (KI) mouse model of cherubism showed that homozygous cherubism mice (Sh3bp2KI/KI) spontaneously develop systemic autoinflammation and inflammatory bone loss and that cherubism is a TNF-α-dependent hematopoietic disorder. In this study, we investigated whether bone marrow transplantation (BMT) is effective for the treatment of inflammation and bone loss in Sh3bp2KI/KI mice. Bone marrow (BM) cells from wild-type (Sh3bp2+/+) mice were transplanted to 6-week-old Sh3bp2KI/KI mice with developing inflammation and to 10-week-old Sh3bp2KI/KI mice with established inflammation. Six-week-old Sh3bp2KI/KI mice transplanted with Sh3bp2+/+ BM cells exhibited improved body weight loss, facial swelling, and survival rate. Inflammatory lesions in the liver and lung as well as bone loss in calvaria and mandibula were ameliorated at 10 weeks after BMT compared to Sh3bp2KI/KI mice transplanted with Sh3bp2KI/KI BM cells. Elevation of serum TNF-α levels was not detected after BMT. BMT was effective for up to 20 weeks in 6-week-old Sh3bp2KI/KI mice transplanted with Sh3bp2+/+ BM cells. BMT also ameliorated the inflammation and bone loss in 10-week-old Sh3bp2KI/KI mice. Thus our study demonstrates that BMT improves the inflammation and bone loss in cherubism mice. BMT may be effective for the treatment of cherubism patients.

Identification of a point mutation in the SH3BP2 gene in cherubism

“…The authors assume that this phenomenon is due to the tissue specificity of the jawbone, which undergoes dynamic growth, such as jawbone growth and tooth eruption, and bone remodeling until adolescence. However, the details of this process have thus far only been reported in mice [14,15], and, due to the rarity of this disease, analyses in humans are not advancing. We expect the spread of diagnosis using molecular biological methods to lead to further advancement in analyses and to clarification of the pathogenesis of cherubism.…”

The bone regenerative capacity of canine mesenchymal stem cells is regulated by site-specific multilineage differentiation

“…42 Furthermore, several bone pathologies display unique radiological and histological features in the jaw. These include fibrous dysplasia of bone 43 cherubism 44 and hyperparathyroid jaw tumor syndrome. 45 Additionally, long-term use of bone antiresorptives is often complicated by jaw osteonecrosis while non-oral bones are spared.…”

Chérubisme : présentation d’un cas clinique suivi pendant 10 ans et revue de littérature

“…Les traitements médicamenteux présentant des effets indésirables potentiels, ils n'ont pas été retenus pour traiter notre patient pendant la phase d'activité qui est restée modérée. Yoshitaka et al suggèrent, à partir d'un modèle murin, qu'une allogreffe de moelle osseuse diminuerait l'inflammation et la résorption osseuse [27]. L'allogreffe de moelle osseuse induisant un traitement immunosupresseur et un risque de réaction du greffon contre l'hôte, elle ne sera pas retenue dans le traitement d'une pathologie bénigne telle que le chérubisme.…”