PTHrP Treatment Fails to Rescue Bone Defects Caused by Hedgehog Pathway Inhibition in Young Mice

Brechbiel, Jillian L.; Ng, Jessica M.Y.; Curran, Tom

doi:10.1177/0192623311399788

Cited by 12 publications

(8 citation statements)

References 45 publications

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“…Although we found that treatment with an IHH signaling inhibitor reduced the formation of chondroma-like lesions in Fgfr3 cKO mice, adverse secondary effects were induced, including premature growth plate fusion leading to a shorter long bone, which is similar to what was observed in mice with chondrocyte-specific deletion of IHH [ 61 ]. Other types of SMOi such as HhAntag had similar effects on the skeleton [ 62 ]. Thus, given that cartilaginous tumors occur mostly in children, caution is required when using SMOi to treat young patients with enchondroma and osteochondroma.…”

Section: Discussionmentioning

confidence: 99%

FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling

et al. 2015

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Most cartilaginous tumors are formed during skeletal development in locations adjacent to growth plates, suggesting that they arise from disordered endochondral bone growth. Fibroblast growth factor receptor (FGFR)3 signaling plays essential roles in this process; however, the role of FGFR3 in cartilaginous tumorigenesis is not known. In this study, we found that postnatal chondrocyte-specific Fgfr3 deletion induced multiple chondroma-like lesions, including enchondromas and osteochondromas, adjacent to disordered growth plates. The lesions showed decreased extracellular signal-regulated kinase (ERK) activity and increased Indian hedgehog (IHH) expression. The same was observed in Fgfr3-deficient primary chondrocytes, in which treatment with a mitogen-activated protein kinase (MEK) inhibitor increased Ihh expression. Importantly, treatment with an inhibitor of IHH signaling reduced the occurrence of chondroma-like lesions in Fgfr3-deficient mice. This is the first study reporting that the loss of Fgfr3 function leads to the formation of chondroma-like lesions via downregulation of MEK/ERK signaling and upregulation of IHH, suggesting that FGFR3 has a tumor suppressor-like function in chondrogenesis.

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Section: Discussionmentioning

confidence: 99%

FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling

et al. 2015

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“…This was particularly important in the development of SMO inhibitors, as fears of developmental bone toxicities, because of the well-known role of the HH pathway in the bone growth plate [ 9 ], were borne out in the clinic [ 10 , 11 ]. This resulted in a Federal Drug Administration restriction on the use of SMO inhibitors in young children prior to completion of bone growth that, unfortunately, was only put in place after bone malformations, first described in young mice [ 12 , 13 ], were recapitulated in children.…”

Section: Target Identificationmentioning

confidence: 99%

Reproducibility of academic preclinical translational research: lessons from the development of Hedgehog pathway inhibitors to treat cancer

Curran¹

2018

Open Biol.

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Academic translational research is growing at a great pace at a time in which questions have been raised about the reproducibility of preclinical findings. The development of Hedgehog (HH) pathway inhibitors for the treatment of cancer over the past two decades offers a case study for understanding the root causes of failure to predict clinical outcomes arising from academic preclinical translational research. Although such inhibitors were once hoped to be efficacious in up to 25% of human cancer, clinical studies showed responses only in basal cell carcinoma and the HH subtype of medulloblastoma. Close examination of the published studies reveals limitations in the models used, lack of quantitative standards, utilization of high drug concentrations associated with non-specific toxicities and improper use of cell line and mouse models. In part, these issues arise from scientific complexity, for example, the failure of tumour cell lines to maintain HH pathway activity in vitro, but a greater contributing factor appears to be the influence of unconscious bias. There was a strong expectation that HH pathway inhibitors would make a profound impact on human cancer and experiments were designed with this assumption in mind.

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“…Ihh acts with PTHrP in a negative feedback loop to regulate early chondrocyte differentiation and hypertrophic differentiation ( 22 ). Blocking Ihh signaling with cyclopamine has been reported to delay chondrocyte hypertrophy in PTHrP knockout embryos, whereas upregulating Ihh signaling in the postnatal cartilage led to accelerated chondrocyte hypertrophy during secondary ossification, indicating that Ihh signaling promotes chondrocyte hypertrophy independently of PTHrP, which may be mediated by Wnt/β-catenin signaling ( 23 , 24 ). As chondrocytes go through a program of proliferation and subsequent differentiation into hypertrophic chondrocytes, PTHrP maintains chondrocyte proliferation and delays their further differentiation ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

The inhibitory roles of Ihh downregulation on chondrocyte growth and differentiation

et al. 2017

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The proliferative rate of chondrocytes affects bone elongation. Chondrocyte hypertrophy is required for endochondral bone formation as chondrocytes secrete factors required for osteoblast differentiation and maturation. Previous studies have demonstrated that the Indian hedgehog (Ihh) signaling pathway is a key regulator of skeletal development and homeostasis. The aim of the present study was to investigate the function of Ihh in chondrocyte proliferation and differentiation, as well as the underlying mechanisms. Ihh was knocked down in mouse chondrocyte cells using short hairpin RNA. Chondrocyte apoptosis and cell cycle arrest were assessed using flow cytometry and the results indicated that knockdown of Ihh significantly inhibited cell growth (P<0.05) and increased apoptosis (P<0.001) compared with negative control cells. Downregulation of Ihh also resulted in cell cycle arrest at G1 to S phase in chondrocytes. It was also observed that knockdown of Ihh decreased alkaline phosphatase activity and mineral deposition of chondrocytes. The inhibitory roles of Ihh downregulation on chondrocyte growth and differentiation may be associated with the transforming growth factor-β/mothers against decapentaplegic and osteoprotegerin/receptor activator of nuclear factor κB ligand signaling pathway. The results of the present study suggest that chondrocyte-derived Ihh is essential for maintaining bone growth plates and that manipulation of Ihh expression or its signaling components may be a novel therapeutic technique for the treatment of skeletal diseases, including achondroplasia.

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PTHrP Treatment Fails to Rescue Bone Defects Caused by Hedgehog Pathway Inhibition in Young Mice

Cited by 12 publications

References 45 publications

FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling

FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling

Reproducibility of academic preclinical translational research: lessons from the development of Hedgehog pathway inhibitors to treat cancer

The inhibitory roles of Ihh downregulation on chondrocyte growth and differentiation

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