Dataset Information

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 (TRAP+) are the exclusive bone-resorbing cells responsible for focal bone destruction in inflammatory arthritis. Recently, a mouse model of cherubism (Sh3bp2KI/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 Sh3bp2KI/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 Sh3bp2KI/KI mice deficient in c-Fos. Resorption pits contained a large number of F4/80+ 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 Sh3bp2KI/KI mice. After activation of the NF-?B pathway, macrophage colony-stimulating factor (M-CSF)-dependent macrophages from c-Fos-deficient Sh3bp2KI/KI mice expressed increased amounts of MMP14 compared with wild-type macrophages. Interestingly, receptor activator of NF-?B ligand (RANKL)-deficient Sh3bp2KI/KI mice failed to show notable bone erosion, whereas c-Fos deletion did restore bone erosion to the RANKL-deficient Sh3bp2KI/KI mice, suggesting that osteolytic transformation of macrophages requires both loss-of-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 Sh3bp2KI/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. © 2017 American Society for Bone and Mineral Research.

SUBMITTER: Kittaka M

PROVIDER: S-EPMC5771992 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Kittaka Mizuho M Mayahara Kotoe K Mukai Tomoyuki T Yoshimoto Tetsuya T Yoshitaka Teruhito T Gorski Jeffrey P JP Ueki Yasuyoshi Y

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20171102 1

Currently, it is believed that osteoclasts positive for tartrate-resistant acid phosphatase (TRAP+) are the exclusive bone-resorbing cells responsible for focal bone destruction in inflammatory arthritis. Recently, a mouse model of cherubism (Sh3bp2<sup>KI/KI</sup> ) 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<sup>KI/KI</sup> mice also deficient in the FBJ osteo ...[more]

PMID: 28914985

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Project description:Cherubism (OMIM#118400) is a craniofacial disorder characterized by destructive jaw expansion. Gain-of-function mutations in SH3-domain binding protein 2 (SH3BP2) are responsible for this rare disorder. We have previously shown that homozygous knock-in (KI) mice (Sh3bp2 KI/KI ) recapitulate human cherubism by developing inflammatory lesions in the jaw. However, it remains unknown why heterozygous KI mice (Sh3bp2 KI/+ ) do not recapitulate the excessive jawbone destruction in human cherubism, even though all mutations are heterozygous in humans. We hypothesized that Sh3bp2 KI/+ mice need to be challenged for developing exacerbated jawbone destruction and that bacterial stimulation in the oral cavity may be involved in the mechanism. In this study, we applied a ligature-induced periodontitis model to Sh3bp2 KI/+ mice to induce inflammatory alveolar bone destruction. Ligature placement induced alveolar bone resorption with gingival inflammation. Quantification of alveolar bone volume revealed that Sh3bp2 KI/+ mice developed more severe bone loss (male: 43.0% ± 10.6%, female: 42.6% ± 10.4%) compared with Sh3bp2 +/+ mice (male: 25.8% ± 4.0%, female: 30.9% ± 6.5%). Measurement of bone loss by the cement-enamel junction-alveolar bone crest distance showed no difference between Sh3bp2 KI/+ and Sh3bp2 +/+ mice. The number of osteoclasts on the alveolar bone surface was higher in male Sh3bp2 KI/+ mice, but not in females, compared with Sh3bp2 +/+ mice. In contrast, inflammatory cytokine levels in gingiva were comparable between Sh3bp2 KI/+ and Sh3bp2 +/+ mice with ligatures. Genetic deletion of the spleen tyrosine kinase in myeloid cells and antibiotic treatment suppressed alveolar bone loss in Sh3bp2 KI/+ mice, suggesting that increased osteoclast differentiation and function mediated by SYK and accumulation of oral bacteria are responsible for the increased alveolar bone loss in Sh3bp2 KI/+ mice with ligature-induced periodontitis. High amounts of oral bacterial load caused by insufficient oral hygiene could be a trigger for the initiation of jawbone destruction in human cherubism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Dataset Information

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

Publications

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

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