Enchondromatosis and Growth Plate Development

Abstract

Purpose of review: Enchondroma is a common cartilage benign tumor that develops from dysregulation of chondrocyte terminal differentiation during growth plate development. Here we provide an overview of recent progress in understanding causative mutations for enchondroma, dysregulated signaling and metabolic pathways in enchondroma, and the progression from enchondroma to malignant chondrosarcoma.

Recent findings: Several signaling pathways that regulate chondrocyte differentiation are dysregulated in enchondromas. Somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) are the most common findings in enchondromas. Mechanisms including metabolic regulation, epigenetic regulation, and altered signaling pathways play a role in enchondroma formation and progression. Multiple pathways regulate growth plate development in a coordinated manner. Deregulation of the process can result in chondrocytes failing to undergo differentiation and the development of enchondroma.

Keywords: Bone development; Cartilage tumors; Cell metabolism; Chondrosarcoma; Enchondroma; Growth plate.

Fig 1:. X-ray photos of patient with enchondromas.

Radiographs from a patient with enchondromatosis. Multiple lesions in the long bones of the femur, tibia (A), and humerus (B) are shown. For the patient in panel A, the lower extremity shows a short limb on the more involved side. The enchondromas are pointed out by arrows.

Fig 2:. Development of enchondrorna and its progression to chondrosarcoma

Enchondroma arises from deregulated chondrocyte differentiation in the growth plate. Defects in chondrocyte terminal differentiation leads to formation of cartilage lesions in the growth plate. When enchondroma occur as multiple lesions, they have a high chance to progress into malignant chondrosarcoma upon secondary mutations. Somatic mutations of IDH1/2 are the most common genetic variations in enchondromas and chondrosarcomas.

Fig 3:. PTHLH-Hedgehog regulation of chondrocyte differentiation.

Regulation of chondrocyte differentiation by Indian Hedgehog (IHH) and parathyroid hormone-like hormone (PTHLH). IHH and PTHLH form a feedback loop and regulate chondrocyte differentiation. IHH secreted by prehypertrophic chondrocytes stimulate perichondral cells to secrete PTHLH, which inhibits hypertrophic differentiation and expression of IHH. IHH could promote chondrocyte differentiation by inhibiting the repressor function of Gli3 and the activator function of Gli2 in a manner that is independent of PTHLH. PTHLH could also suppress hypertrophic differentiation independent of IHH by through regulating Gli3 repressor function and promoting protein Idnase A (PKA). PICA signaling leads to activation of histone deacetylase 4 (HDAC4), which inhibits Mef2 function.

Fig 4:. Function of wildtype and mutant IDH enzymes.

Wild type isocitrate dehydrogenases catalyze reversible conversion between isocitrate and α-ketoglutarate (a-KG). IDH1 is present in the cytosol, and IDH2 and IDH3 localize in the mitochondria. In the majority of enchondromas, somatic mutations of IDH1 or IDH2 are present in chondrocytes. mut-IDH1 and mut-IDH2 lost their original function and gain a neomorphic function that converts α-ketoglutarate to D-2-hydroxyglutarate (D-2HG).