NFAT restricts osteochondroma formation from entheseal progenitors
Xianpeng Ge, Kelly Tsang, Lizhi He, Roberto A. Garcia, Joerg Ermann, Fumitaka Mizoguchi, Minjie Zhang, Bin Zhou, Bin Zhou, Antonios O. Aliprantis
Xianpeng Ge, Kelly Tsang, Lizhi He, Roberto A. Garcia, Joerg Ermann, Fumitaka Mizoguchi, Minjie Zhang, Bin Zhou, Bin Zhou, Antonios O. Aliprantis
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Research Article Bone biology

NFAT restricts osteochondroma formation from entheseal progenitors

Abstract

Osteochondromas are common benign osteocartilaginous tumors in children and adolescents characterized by cartilage-capped bony projections on the surface of bones. These tumors often cause pain, deformity, fracture, and musculoskeletal dysfunction, and they occasionally undergo malignant transformation. The pathogenesis of osteochondromas remains poorly understood. Here, we demonstrate that nuclear factor of activated T cells c1 and c2 (NFATc1 and NFATc2) suppress osteochondromagenesis through individual and combinatorial mechanisms. In mice, conditional deletion of NFATc1 in mesenchymal limb progenitors, Scleraxis-expressing (Scx-expressing) tendoligamentous cells, or postnatally in Aggrecan-expressing cells resulted in osteochondroma formation at entheses, the insertion sites of ligaments and tendons onto bone. Combinatorial deletion of NFATc1 and NFATc2 gave rise to larger and more numerous osteochondromas in inverse proportion to gene dosage. A population of entheseal NFATc1- and Aggrecan-expressing cells was identified as the osteochondroma precursor, previously believed to be growth plate derived or perichondrium derived. Mechanistically, we show that NFATc1 restricts the proliferation and chondrogenesis of osteochondroma precursors. In contrast, NFATc2 preferentially inhibits chondrocyte hypertrophy and osteogenesis. Together, our findings identify and characterize a mechanism of osteochondroma formation and suggest that regulating NFAT activity is a new therapeutic approach for skeletal diseases characterized by defective or exaggerated osteochondral growth.

Authors

Xianpeng Ge, Kelly Tsang, Lizhi He, Roberto A. Garcia, Joerg Ermann, Fumitaka Mizoguchi, Minjie Zhang, Bin Zhou, Bin Zhou, Antonios O. Aliprantis

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Figure 4

Osteochondroma formation at other locations after combinatorial deletion of nuclear factor of activated T cells c1 and c2 (Nfatc1 and Nfatc2) in postnatal Aggrecan-expressing cells.

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Osteochondroma formation at other locations after combinatorial deletion...
(A) Quantification of osteochondromas around hip joints 1 (n = 10, 10, 7, and 11 for Nfatc1fl/flNfatc2+/–, Nfatc1AggCreERNfatc2+/–, Nfatc1fl/flNfatc2–/–, and Nfatc1AggCreERNfatc2–/– mice, respectively) and 3 (n = 10, 10, 11, and 14 animals, respectively) months after tamoxifen pulse in 8- or 12-week-old mice. One-way ANOVA followed by Tukey’s test were performed. (B) Ex vivo μCT images and safranin O/fast green–stained histology of the hip joints of mice with the indicated genotypes 3 months after tamoxifen administration to 8- or 12-week-old mice. Arrows, osteochondromas. (C) Representative μCT images showing osteochondroma formation at the epiphyses of knee joints (arrows). (D and E) Representative μCT images of osteochondroma formation at distal and proximal femurs (arrows). (F and G) Representative μCT images of osteochondromas around shoulder joins (F, circles), at the proximal humerus (F, arrows), and at the scapula (G). Scale bars: 1.0 mm (except in B, lower panels, 100 μm).