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 1

Ablation of nuclear factor of activated T cells c1 (NFATc1) in limb mesenchymal progenitors and postnatal Aggrecan-expressing cells causes osteochondromas at entheseal sites.

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Ablation of nuclear factor of activated T cells c1 (NFATc1) in limb mese...
(A) Gross (left panels) and 3-D μCT images (right panels) showing ectopic osteocartilaginous outgrowths (arrows) at the proximal tibia of 16-week-old Nfatc1Prx1 mice. Scale bars: 1.0 mm. Images are representative of 8 mice per genotype. (B) Safranin O/fast green stain of coronal sections of mouse knee joints showing abnormal outgrowths in Nfatc1Prx1 mice located at the tibial medial collateral ligament (MCL) enthesis and displaying features of osteochondromas, including a cartilaginous cap (*) and the marrow cavity (#), continuous with that of underlying bone. Scale bars: 100 μm. (C) Illustration showing tamoxifen-induced Cre-mediated recombination of the mTmG reporter allele in Aggrecan+ cells from Aggrecan-CreERT2;Rosa26-mTmGfl/+ (AggCreER;mTmG) mice leading to membrane GFP expression (upper left panel). GFP fluorescence in the growth plate (GP, lower left panel), articular cartilage, meniscus (M, upper right panel), and a subset of cells at the tibial MCL enthesis (lower right panel) in AggCreER;mTmG mice 1 month after tamoxifen administration. Scale bars: 100 μm. CB, cortical bone. Images are representative of 5 mice. (D) In vivo (left and middle panels) and ex vivo (right panels) 3-D μCT images showing osteochondroma formation at the tibial MCL enthesis (arrows) 1 and 3 months after tamoxifen pulse of an 8-week-old Nfatc1AggCreER mouse. Scale bars: 5.0 mm (left and middle panels), 1.0 mm (right panels). Images are representative of 10 mice per genotype.