Nutrient-regulated dynamics of chondroprogenitors in the postnatal murine growth plate

Abstract

Longitudinal bone growth relies on endochondral ossification in the cartilaginous growth plate where chondrocytes accumulate and synthesize the matrix scaffold that is replaced by bone. The chondroprogenitors in the resting zone maintain the continuous turnover of chondrocytes in the growth plate. Malnutrition is a leading cause of growth retardation in children; however, after recovery from nutrient deprivation, bone growth is accelerated beyond the normal rate, a phenomenon termed catch-up growth. Though nutritional status is a known regulator of long bone growth, it is largely unknown if and how chondroprogenitor cells respond to deviations in nutrient availability. Here, using fate-mapping analysis in Axin2CreERT2 mice, we showed that dietary restriction increased the number of Axin2+ chondroprogenitors in the resting zone and simultaneously inhibited their differentiation. Once nutrient deficiency was resolved, the accumulated chondroprogenitor cells immediately restarted differentiation and formed chondrocyte columns, contributing to accelerated growth. Furthermore, we showed that nutrient deprivation reduced the level of phosphorylated Akt in the resting zone, and that exogenous IGF-1 canceled this reduction and stimulated differentiation of the pooled chondroprogenitors, decreasing their numbers. Our study ofAxin2CreERT2revealed that nutrient availability regulates the balance between accumulation and differentiation of chondroprogenitors in the growth plate, and further demonstrated that IGF-1 partially mediates this regulation by promoting the committed differentiation of the chondroprogenitor cells.

Compensatory growth and recovery of cartilage cytoarchitecture after transient cell death in fetal mouse limbs

“…The retention of EdU + cells in the RZ during the early phase of the recovery (Fig. 5b) resembled the enhanced self-renewal of Axin2 + chondroprogenitors observed during transient diet restriction in juvenile mice 28 . Since the capability of self-renewal in chondroprogenitors has been shown to appear only at postnatal stages 35 , one possible explanation was that self-renewal had been precociously activated upon injury.…”

“…1b"). As mentioned above, the latter scenario was recently found in the case of catch-up growth induced by transient diet restriction 28 . In ), using up their potential faster (eventually failing to catch-up).…”

“…In resting cells, IGF1 promotes the recruitment towards proliferative chondrocytes, for example by repressing expression of PTHrP 48 . In addition, Oichi et al showed that, during dietary restriction in juvenile mice, Axin2 + progenitors in the cartilage were biased towards self-renewal instead of transitioning to the proliferative pool, which associated with decreased expression of Igf1 in the resting zone 28 . Conversely, this bias and the reduced expression of Igf1 were reversed when the food supply was restored, leading to catch-up growth 28 .…”

“…In ), using up their potential faster (eventually failing to catch-up). Alternatively, chondroprogenitors first self-renew (b"), as shown by Oichi et al 28 , and then continue proliferating, leading to catch-up after a delay. contrast, we unexpectedly found that a hybrid compensatory growth took place via two mechanisms: (1) replenishment of resting chondrocytes due to a transient bias towards self-renewal, followed by accelerated transition to the proliferative pool, but insufficient to gain back the lost size; (2) transiently increased HTC size.…”

Depletion of SMN Protein in Mesenchymal Progenitors Impairs the Development of Bone and Neuromuscular Junction in Spinal Muscular Atrophy

“…The chondrocytespecific Igf1 knockout mouse demonstrated a reduction in postnatal body and femur length, and the chondrocyte-specific Igf1r knockout mouse demonstrated a significant reduction in bone growth, as well as a decrease in both growth plate proliferative and hypertrophic zone (Govoni et al, 2007;Wang et al 2011). A recent study revealed that resting zone chondrocytes in the growth plate serve as a major source of local IGF and activate the p-AKT pathway via autocrine and paracrine IGF signaling (Oichi et al, 2023). The study further revealed that cells that constitute bone and bone marrow, apart from chondrocytes, do not express Igf1, making chondrocytes the solitary source of local IGF.…”