Background/Purpose: A gain-of-function mutation in the adaptor Src Homology 3 Binding Protein 2 (SH3BP2) causes Cherubism, a rare pediatric disease marked by aggressive bone remodeling in the mandible and maxilla.  Mice homozygous for the most common Cherubism mutation (Sh3bp2^KI/KI) display TNFa-dependent osteopenia and inflammatory arthritis with peri-articular bone erosions. We sought to investigate whether bone-resorbing osteoclasts are key cellular mediators of the systemic bone loss and local inflammatory erosion observed in this model.  To this end, Sh3bp2^KI/KI mice with an inducible mutation in Rank, encoding a master regulator of osteoclast differentiation, were generated.

Methods: We generated Sh3bp2^KI/KI RANK-deficient mice using Mx1-Cre driven deletion of floxed Rank alleles after intra-peritoneal injection of poly-IC at 10-days of age (referred to as Sh3bp2^KI/KI Rank^Δ/Δ).  Control mice, also treated with poly-IC, included Sh3bp2^KI/KI Rank^fl/fl without the Mx1-Cre transgene, Sh3bp2^+/+Rank^fl/fl and Sh3bp2^+/+ Rank^Δ/Δ.  Bone mass, peri-articular erosions and synovitis were assessed by a combination of micro-computed tomography (mCT) and histology at 12 weeks of age.

Results: Neither Sh3bp2^+/+Rank^fl/fl nor Sh3bp2^+/+ Rank^Δ/Δ displayed inflammatory arthritis or bone erosion. Sh3bp2^+/+ Rank^Δ/Δ developed severe osteopetrosis, consistent with osteoclast-deficiency. As previously reported, Sh3bp2^KI/KI sufficient for RANK (Sh3bp2^KI/KI Rank^fl/fl) developed osteopenia and inflammatory arthritis at the elbow joint with marked peri-articular erosions.  Depletion of osteoclasts by genetic deletion of Rank reversed the systemic osteopenia observed in Sh3bp2^KI/KI mice but had no effect on synovitis at the elbow.  Unexpectantly, peri-articular erosions at the elbow joints were not ameliorated in Sh3bp2^KI/KI Rank^Δ/Δ mice despite a significant reduction in tartrate-resistant acid phosphatase (TRAP) positive osteoclasts.

Conclusion:   Deletion of Rank inhibits osteoclastogenesis and reverses systemic osteopenia in Sh3bp2^KI/KI mice.  In contrast, while the loss Rank reduces classic TRAP-positive osteoclasts at the inflamed elbow joints of Sh3bp2^KI/KI mice, it does not reduce local bone erosion. These intriguing findings suggest an alternative pathway to bone erosion exists in the Sh3bp2^KI/KI model of inflammatory arthritis that is independent of RANK.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evidence-for-receptor-activator-of-nf-kb-rank-independent-bone-erosion-in-the-cherubism-mouse-model-of-inflammatory-arthritis/