Background/Purpose:

Osteochondromas are the most common benign bone tumor and are characterized by cartilage-capped bony projections from the external surface of bone. These lesions may cause pain, deformity, fracture and neurovascular compromise, and rarely undergo malignant transformation. The pathogenesis of osteochondroma remains poorly understood. Since we recently reported that transcription factor nuclear factor of activated T cells c1 (NFATc1) suppresses osteoarthritis in mice, we hypothesized that it controls other aspects of chondrocyte biology. The objective of this study was to further characterize potential roles of NFATc1 in mesenchymal progenitors and chondrocytes.

Methods:

To investigate the role of NFATc1 in mesenchymal progenitors of the limb bud and in postnatal chondrocytes, Nfatc1^fl/fl mice were bred to Prx1-Cre (hereafter Nfatc1^Prx1) or tamoxifen-inducible Aggrecan-CreER^T2 (hereafter Nfatc1^{Aggrecan-CreER}) mice, respectively. Nfatc1^{Aggrecan-CreER} mice were analyzed on either an NFATc2-sufficient (Nfatc2^+/-) or deficient (Nfatc2^-/-) background to check for redundancy among NFAT family members. Nfatc1 was deleted in Nfatc1^{Aggrecan-CreER} chondrocytes by administration of tamoxifen at 8 weeks or 12 weeks of age. The skeletal and joint phenotypes of these strains were determined by a combination of micro-CT and histology.

Results:

Nfatc1^Prx1 mice displayed ectopic cartilage and bone formation around the knee joints (osteochondromatosis) at 16 weeks of age. Similarly, within 1 month of tamoxifen injection, all Nfatc1^{aggrecan-creER}Nfatc2^+/- mice displayed ectopic cartilage formation at the tibial attachment site of the medial collateral ligament. Three months after the administration of tamoxifen, Nfatc1^{aggrecan-creER}Nfatc2^+/- mice showed clear osteochondroma-like exostoses at the ligament-bone attachment site, characterized histologically by cartilage-capped bony protrusions continuous with underlying bone. In some Nfatc1^{aggrecan-creER}Nfatc2^+/- mice, cartilaginous protrusions outgrew from the epiphyses of knee joints at this time point. Lastly, the osteochondromagenesis previously reported around the hip joints in Nfatc2^-/- mice, was exacerbated in Nfatc1^{aggrecan-creER}Nfatc2^-/- double knockout mice.

Conclusion:

Our data indicate that NFATc1 constitutively represses chondrogenesis and the formation of exostoses in mice. Reducing NFATc1 expression in mesenchymal progenitors or postnatal aggrecan-expressing chondrocytes represents a novel animal model of osteochondromagenesis.

---

« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-mouse-model-of-osteochondromagenesis-by-deleting-nfatc1-in-mesenchymal-progenitors-and-postnatal-chondrocytes/