Cherubism Mice Also Deficient in c-Fos Exhibit Inflammatory Bone Destruction Executed by Macrophages That Express MMP14 Despite the Absence of TRAP+ Osteoclasts

Abstract

Currently, it is believed that osteoclasts positive for tartrate-resistant acid phosphatase (TRAPþ) are the exclusive bone-resorbing cells responsible for focal bone destruction in inflammatory arthritis. Recently, a mouse model of cherubism (Sh3bp2 KI/KI ) with a homozygous gain-of-function mutation in the SH3-domain binding protein 2 (SH3BP2) was shown to develop auto-inflammatory joint destruction. Here, we demonstrate that Sh3bp2 KI/KI mice also deficient in the FBJ osteosarcoma oncogene (c-Fos) still exhibit noticeable bone erosion at the distal tibia even in the absence of osteoclasts at 12 weeks old. Levels of serum collagen I C-terminal telopeptide (ICTP), a marker of bone resorption generated by matrix metalloproteinases (MMPs), were elevated, whereas levels of serum cross-linked C-telopeptide (CTX), another resorption marker produced by cathepsin K, were not increased. Collagenolytic MMP levels were increased in the inflamed joints of the Sh3bp2 KI/KI mice deficient in c-Fos. Resorption pits contained a large number of F4/80þ macrophages and genetic depletion of macrophages rescued these erosive changes. Importantly, administration of NSC405020, an MMP14 inhibitor targeted to the hemopexin (PEX) domain, suppressed bone erosion in c-Fos-deficient Sh3bp2 KI/KI mice. After activation of the NF-kB pathway, macrophage colony-stimulating factor (M-CSF)-dependent macrophages from c-Fosdeficient Sh3bp2 KI/KI mice expressed increased amounts of MMP14 compared with wild-type macrophages. Interestingly, receptor activator of NF-kB ligand (RANKL)-deficient Sh3bp2 KI/KI mice failed to show notable bone erosion, whereas c-Fos deletion did restore bone erosion to the RANKL-deficient Sh3bp2 KI/KI mice, suggesting that osteolytic transformation of macrophages requires both lossof-function of c-Fos and gain-of-function of SH3BP2 in this model. These data provide the first genetic evidence that cells other than osteoclasts can cause focal bone destruction in inflammatory bone disease and suggest that MMP14 is a key mediator conferring pathological bone-resorbing capacity on c-Fos-deficient Sh3bp2 KI/KI macrophages. In summary, the paradigm that osteoclasts are the exclusive cells executing inflammatory bone destruction may need to be reevaluated based on our findings with c-Fos-deficient cherubism mice lacking osteoclasts.

Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis

“…Macrophages are considered to serve essential functions in RA pathogenesis because they are the main producers of pro‐inflammatory cytokines that promote inflammation . The number of synovial macrophages is correlated with the clinical disease activity, and selective macrophage depletion has a strong anti‐inflammatory effect in animal models of arthritis . Generally, M1 macrophages are pro‐inflammatory, whereas M2 macrophages are anti‐inflammatory.…”

“…(36) The number of synovial macrophages is correlated with the clinical disease activity, and selective macrophage depletion has a strong anti-inflammatory effect in animal models of arthritis. (46) Generally, M1 macrophages are pro-inflammatory, whereas M2 macrophages are anti-inflammatory. In the present study, we found that numerous M1-like macrophages accumulated in the synovium of the CIA mice, whereas JWH133 treatment obviously reduced the RA-induced increase in M1-like macrophages and enhanced the amount of M2-like macrophages.…”

Septin2 mediates podosome maturation and endothelial cell invasion associated with angiogenesis

“…S1 F). Furthermore, treatment with an inhibitor specific for MT1-MMP (NSC405020; Kittaka et al, 2018) decreased podosome function to the same extent (Fig. S1 F), indicating that MT1-MMP is the predominant enzyme responsible for the observed Src-induced podosomal matrix degradation.…”

Tankyrase (PARP5) Inhibition Induces Bone Loss through Accumulation of Its Substrate SH3BP2

“…Analysis of the SH3BP2 cherubism mutant mice revealed that heterozygous mice exhibit osteopenia owing to increased osteoclast formation, whereas homozygous mutant mice spontaneously develop systemic organ inflammation and severe osteopenia [52]. The mutant macrophages are hypersensitive to receptor activator NF-κB ligand (RANKL) and tumor necrosis factor (TNF), leading to the production of a large number of osteoclasts [52,57,65,66,67]. In the mutant cells, accumulated SH3BP2 proteins enhance phosphorylation of SYK in response to RANKL and TNF, and subsequently activate NFATc1, which is a master regulator of osteoclastogenesis [52,57].…”