Activation of mTORC1 in chondrocytes does not affect proliferation or differentiation, but causes the resting zone of the growth plate to become disordered

Abstract

There are several pitfalls associated with research based on transgenic mice. Here, we describe our interpretation and analysis of mTORC1 activation in growth plate chondrocytes and compare these to a recent publication (Yan et al., Nature Communications 2016, 7:11151). Both laboratories employed TSC1-floxed mice crossed with collagen type 2-driven Cre (Col2-Cre), but drew substantially different conclusions. It was reported that activation of mechanistic target of rapamycin complex 1 (mTORC1) via Tsc1 ablation promotes the hypertrophy of growth plate chondrocytes, whereas we observe only disorganization in the resting zone, with no effect on chondrocyte hypertrophy or proliferation. Here, we present our data and discuss the differences in comparison to the earlier phenotypic characterization of TSC1 ablation in cartilage. Importantly, we detect Col2-Cre activity in non-cartilaginous tissues (including the brain) and discuss it in relation to other studies reporting non-cartilaginous expression of collagen alpha(1) II. Altogether, we conclude that mouse phenotypes following genetic ablation using Col2-Cre should be interpreted with care. We also conclude that activation of mTORC1 by TSC1 ablation in postnatal chondrocytes with inducible Col2-Cre (Col2-CreERt) leads to disorganization of the resting zone but causes no changes in chondrocyte proliferation or differentiation.

Schwann cell precursors contribute to skeletal formation during embryonic development in mice and zebrafish

“…In support of this, we detected no NCC contribution to the limbs upon inducing recombination in these cells by injecting tamoxifen into Sox10 CreERT2 ;R26R Confetti mice at E8.5, in line with the classical view concerning tissues to which NCCs contribute (50). As we discussed recently, genetic experiments with noninducible Cre mice must be interpreted carefully, due to potential nonspecific promoter activity during ontogenesis (51).…”

Postnatal skeletal growth is driven by the epiphyseal stem cell niche: potential implications to pediatrics

“…46 In genetic experiments the activation of mTORC1 does not lead to bone elongation, perhaps due to the gradual disorganization of the growth plate. 47 However, temporal activation of mTORC1, such as with high levels of amino acids or IGF1 (both major activators of mTORC1), may, in theory, increase the number of the epiphyseal stem cells.…”

Understanding the Cellular and Molecular Mechanisms That Control Early Cell Fate Decisions During Appendicular Skeletogenesis

“…This suggests that IHH controls the proliferation of skeletal stem cells (Newton et al, 2019). On the other hand, it has been reported that activation of mTORC1 (Newton et al, 2018) controls the organization of the resting zone without affecting cell proliferation. Activation of this signalling pathway regulates stem cell renewal because it controls the transition of skeletal stem cell division from asymmetric to symmetric.…”