Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency

Abstract

Mutations in the a disintegrin and metalloproteinase with thrombospondin motif–like 2 (ADAMTSL2) gene are responsible for the autosomal recessive form of geleophysic dysplasia, which is characterized by short stature, short extremities, and skeletal abnormalities. However, the exact function of ADAMTSL2 is unknown. To elucidate the role of this protein in skeletal development, we generated complementary knockout (KO) mouse models with either total or chondrocyte Adamtsl2 deficiency. We observed that the Adamtsl2 KO mice displayed skeletal abnormalities reminiscent of the human phenotype. Adamtsl2 deletion affected the growth plate formation with abnormal differentiation and proliferation of chondrocytes. In addition, a TGF‐β signaling impairment in limbs lacking Adamtsl2 was demonstrated. Further investigations revealed that Adamtsl2 KO chondrocytes failed to establish a microfibrillar network composed by fibrillin1 and latent TGF‐β binding protein 1 fibrils. Chondrocyte Adamtsl2 KO mice also exhibited dwarfism. These studies uncover the function of Adamtsl2 in the maintenance of the growth plate ECM by modulating the microfibrillar network.—Delhon, L., Mahaut, C., Goudin, N., Gaudas, E., Piquand, K., Le Goff, W., Cormier‐Daire, V., Le Goff, C. Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency. FASEB J. 33, 2707–2718 (2019). http://www.fasebj.org

Acromelic dysplasias: how rare musculoskeletal disorders reveal biological functions of extracellular matrix proteins

“…Global Adamtsl2 deletion by homologous recombination resulted in >90% perinatal lethality due to bronchial occlusion and a ventricular septal defect. 37,38 Very few mice survived after several days and they were significantly smaller and had tight skin and stiff limbs that collectively severely restricted movement (unpublished data). In addition, a subset of Adamtsl2 heterozygous mice developed thicker skin with elevated collagen deposition, indicative of a fibrotic response.…”

“…37 Conditional deletion of Adamtsl2 in the limbs using Prx1-Cre or in the growth plate using Col2a-Cre recapitulated some of the musculoskeletal phe-notypes described in individuals with GD, such as limb shortening. 38,39 Surprisingly, Scx-Cremediated deletion of Adamtsl2 in tendon, the site of the strongest Adamtsl2 expression in the mouse limb, also resulted in shortened limbs, concomitant with a 20-30% reduction in Achilles tendon length. 39 Mechanistically, however, different explanations of the short limb phenotypes in the two mouse models were provided.…”

“…Both signaling pathways appear to be dysregulated in patient-derived fibroblasts and mouse models for some of the acromelic dysplasias, such as the Adamts10 and Adamts17 knockouts and the cartilage-specific deletion of Adamtsl2. 12,38,44,45,64 In the following section, we describe in more detail the structure and function of the proteins that are encoded by the genes mutated in acromelic dysplasias.…”

The quest for substrates and binding partners: A critical barrier for understanding the role of ADAMTS proteases in musculoskeletal development and disease

“…96,112 Research of ADAMTSL protein functions suggests predominantly ECM localization and relevance in ECM growth factor regulation. 117,[123][124][125][126]…”

“…In addition, commonality between phenotypes due to mutations in ADAMTS proteases, ADAMTSL proteins, and FBN1, such as in acromelic dysplasias and ectopia lentis suggests linkage in relevant human disorders and extends the demarcation of ADAMTS substrate interactions to possibly include non‐cleaved substrates 96,112 . Research of ADAMTSL protein functions suggests predominantly ECM localization and relevance in ECM growth factor regulation 117,123‐126 …”