Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

Abstract

Chondrocytes interact with their neighbours through their cartilaginous extracellular matrix (ECM).Chondrocyte-matrix interactions compensate the lack of cell-cell contact and are modulated by proteoglycans and other molecules. The epiphyseal growth plate is a highly organized tissue responsible for long bone elongation. The growth plate is regulated by gradients of morphogens that are established by proteoglycans. Morphogens diffuse across the ECM, creating short-and long-range signalling that lead to the formation of a polarized tissue. Mutations affecting genes that modulate cell-matrix interactions are linked to several human disorders. Homozygous mutations of EXT1/EXT2 result in reduced synthesis and shortened heparan sulphate chains on both cell surface and matrix proteoglycans. This disrupts the diffusion gradients of morphogens and signal transduction in the epiphyseal growth plate, contributing to loss of cell polarity and osteochondroma formation. Osteochondromas are cartilage-capped bony projections arising from the metaphyses of endochondral bones adjacent to the growth plate. The osteochondroma cap is formed by cells with homozygous mutation of EXT1/EXT2 and committed stem cells/wild-type chondrocytes. Osteochondroma serves as a niche (a permissive environment), which facilitates the committed stem cells/wild-type chondrocytes to acquire secondary genetic changes to form a secondary peripheral chondrosarcoma. In such a scenario, the micro-environment is the site of the initiating processes that ultimately lead to cancer.

Alelo doble mutante en el gen EXT1 no informado previamente en una adolescente con exostosis múltiple hereditaria

“…Presentan una incidencia estimada que va de 1/18 000 a 1/50 000 casos en los países europeos. 5 Son causadas principalmente por mutaciones en genes supresores de tumores, como el EXT1, localizado en 8q24.11, que causa la EMH tipo 1 (OMIM 133700); el EXT2, ubicado en 11p11.2, que causa la EMH tipo 2 (OMIM 133701); y la EMH tipo 3 (OMIM 600209), cuyo locus ha sido localizado en el brazo corto del cromosoma 19 (19p), pero aún no se han detectado alteraciones de este. 1,6,7 Las mutaciones en EXT1 representan entre 56 y 78% Se presenta el caso de una adolescente evaluada de forma multidisciplinaria con diagnóstico clínico, estudio radiológico y molecular de EMH con doble alelo mutante en el gen EXT1 no informado previamente.…”

Multiple Roles of the SO42−/Cl−/OH− Exchanger Protein Slc26a2 in Chondrocyte Functions

“…Chondrocytes are derived from mesenchymal progenitor cells. Bone formation is initiated when activation of cartilage-specific genes causes mesenchymal cell condensation and differentiation into chondrocytes (3). These chondrocytes form a cartilaginous template using abundant extracellular matrix (ECM) 3 comprised of proteoglycans.…”

“…Bone formation is initiated when activation of cartilage-specific genes causes mesenchymal cell condensation and differentiation into chondrocytes (3). These chondrocytes form a cartilaginous template using abundant extracellular matrix (ECM) 3 comprised of proteoglycans. The ECM surrounds mature chondrocytes and mediates cell-cell contacts (3,4).…”

“…These chondrocytes form a cartilaginous template using abundant extracellular matrix (ECM) 3 comprised of proteoglycans. The ECM surrounds mature chondrocytes and mediates cell-cell contacts (3,4).…”

“…Long bone elongation requires chondrocyte proliferation, differentiation, and secretion of ECM to form the growth plate cartilage (3). The growth plate is divided into three distinct zones: the resting, proliferating, and mineralization zones (5).…”