Suppressor of fused-restrained Hedgehog signaling in chondrocytes is critical for epiphyseal growth plate maintenance and limb elongation in juvenile mice

Abstract

Hedgehog (Hh) signaling plays multiple critical roles in regulating chondrocyte proliferation and differentiation during epiphyseal cartilage development. However, it is still unclear whether Hh signaling in chondrocytes is required for growth plate maintenance during juvenile growth, and whether sustained activation of Hh signaling in chondrocytes promotes limb elongation. In this study, we first utilized Hh reporter mice to reveal that Hh signaling was activated in resting and columnar chondrocytes in growth plates of juvenile and adult mice. Next, we genetically modulated Hh signaling by conditionally deleting Smo or Sufu in all or a subpopulation of growth plate chondrocytes, and found that ablation of either Smo or Sufu in chondrocytes of juvenile mice caused premature closure of growth plates and shorter limbs, whereas Osx-Cre-mediated deletion of either of these two genes in prehypertrophic chondrocytes did not lead to obvious growth plate defects, indicating that Hh signaling mainly functions in resting and/or columnar chondrocytes to maintain growth plates at the juvenile stage. At the cellular level, we found that chondrocyte-specific ablation of Smo or Sufu accelerated or suppressed chondrocyte hypertrophy, respectively, whereas both decreased chondrocyte proliferation and survival. Thus, our study provided the first genetic evidence to establish the essential cell-autonomous roles for tightly-regulated Hh signaling in epiphyseal growth plate maintenance and limb elongation during juvenile growth.

Gli1 labels progenitors during chondrogenesis in postnatal mice

“…The restraint of IHH activity level was critical for epiphyseal growth plate maintenance and limb elongation in mice. Chondrocyte-specific deletion of Smo or Sufu in growth plate chondrocytes to defects in epiphyseal growth plates and limb elongation (Xiu et al, 2022 ).…”

“…After the juvenile stage, TSC1 deletion in chondrogenic progenitors led to overactive mTORC1 activity and promoted stem-cell-like cells from the RZ generating more columnar chondrocytes (Newton et al, 2019 ). The IHH signals also regulate chondrocyte behavior, abnormal level of which leads to growth plate defect (Xiu et al, 2022 ). It is also interesting to know the effect of hyperactivation or inactivation of IHH in Gli1+ CPs, which needs to be further investigated.…”

Intervertebral disc-intrinsic Hedgehog signaling maintains disc cell phenotypes and prevents disc degeneration through both cell autonomous and non-autonomous mechanisms

“…To evaluate the targeting efficiency and specificity of Krt19-CreER in the IVDs, Krt19-CreER mice were bred with R26-tdTomato reporter mice to produce Krt19-CreER ; R26-tdTomato mice. All above mice and their littermate controls were injected with tamoxifen at 2 weeks of age according to our previously described procedures [ 27 ]. To evaluate the effect of pharmacological inhibition of Hh signaling on the health of IVDs, ten 2-week-old C57BL/6 mice were randomly divided into two groups, and orally administered with either 50 mg/kg vismodegib (GDC) or vehicle solution (vehicle) as described previously [ 28 ].…”

Primary cilium–mediated mechanotransduction in cartilage chondrocytes

“…Interestingly, ablations of both Smo and SUFU decrease the growth, proliferation, differentiation, and survival of the cell. 36 In addition, OA is associated with abnormal Hh signaling or chondrocyte hypertrophy. 37 A previous study has shown that mechanical cues promote the Hh signaling and ADAMTS-5 expression in OA and exercise-induced muscle hypertrophy in satellite cells.…”