Pharmacological intervention of the FGF-PTH axis as a potential therapeutic for craniofacial ciliopathies

Disease models & mechanisms

2022 Jul 12

Paese, CLB;Chang, CF;Kristeková, D;Brugmann, SA;
PMID: 35818799 | DOI: 10.1242/dmm.049611

Ciliopathies represent a disease class characterized by a broad range of phenotypes including polycystic kidneys and skeletal anomalies. Ciliopathic skeletal phenotypes are among the most common and most difficult to treat due to a poor understanding of the pathological mechanisms leading to disease. Using an avian model (talpid2) for a human ciliopathy with both kidney and skeletal anomalies (Orofaciodigital syndrome 14), we identified disruptions in the FGF23-PTH axis that resulted in reduced calcium uptake in the developing mandible and subsequent micrognathia. While pharmacological intervention with the FDA-approved pan-FGFR inhibitor AZD4547 alone rescued expression of the FGF target Sprouty2, it did not significantly rescue micrognathia. In contrast, treatment with a cocktail of AZD4547 and Teriparatide acetate, a PTH agonist and FDA-approved treatment for osteoporosis, resulted in a molecular, cellular, and phenotypic rescue of ciliopathic micrognathia in talpid2 mutants. Together, these data provide novel insight into pathological molecular mechanisms associated with ciliopathic skeletal phenotypes and a potential therapeutic strategy for a pleiotropic disease class with limited to no treatment options.

Molecular profiles of oxyphilic and chief cell parathyroid adenoma.

Mol Cell Endocrinol.

2017 Oct 03

Lu M, Kjellin H, Fotouhi O, Lee L, Nilsson IL, Haglund F, Höög A, Lehtiö J, Larsson C.
PMID: 28986304 | DOI: 10.1016/j.mce.2017.10.001

Abstract

CONTEXT:

Parathyroid adenomas may be composed of chief cells (conventional or water-clear), oxyphilic cells or a mixture of both cells. The molecular background is rarely studied.

OBJECTIVE:

To molecularly characterize parathyroid adenomas of different cell type composition.

DESIGN:

Chief and oxyphilic cell adenomas were compared in a cohort of 664 sporadic cases. Extensive analyses of parathyroid tissueswere performed in subgroup. Gene expressions of known parathyroid-related genes were quantified by qRT-PCR. Protein expression profiles determined by liquid chromatography - tandem mass spectrometry (LC-MS/MS) were compared between each type of parathyroid adenomas. Selected proteins were analysed by Western blot and immunohistochemistry.

RESULTS:

Patients with oxyphilic cell adenoma were found to be older at the time of operation than chief cell adenoma cases but did not differ in gender, serum calcium or tumor weight. The gene expression of CASR, VDR, FGFR1, CYP27B1, CYP24A1, PTHLH, GCM2, NDUFA13, CDKN1B, MEN1 and CNND1 did not differ between the groups. VDR protein levels were weaker in oxyphilic adenomas. The proteomic studies identified a set of novel dysregulated proteins of interest such as nuclear receptor subfamily 2 group C member 2 (TR4), LIM domain only protein 3 (LMO3) and calcium-binding protein B (S100B). LMO3 and S100B showed higher expression in oxyphilic adenoma and may be involve in parathyroid tumorgenesis through the p53 pathway. TR4 showed different subcellular localisation between adenoma and normal rim.

CONCLUSION:

Chief and oxyphilic cell parathyroid adenomas have partly overlapping but also distinct molecular profiles. The calmodulin-eEF2K, TR4 and p53 pathways may be involved in the tumor development.

Altered developmental programs and oriented cell divisions lead to bulky bones during salamander limb regeneration

Nature communications

2022 Nov 14

Kaucka, M;Joven Araus, A;Tesarova, M;Currie, JD;Boström, J;Kavkova, M;Petersen, J;Yao, Z;Bouchnita, A;Hellander, A;Zikmund, T;Elewa, A;Newton, PT;Fei, JF;Chagin, AS;Fried, K;Tanaka, EM;Kaiser, J;Simon, A;Adameyko, I;
PMID: 36376278 | DOI: 10.1038/s41467-022-34266-w

There are major differences in duration and scale at which limb development and regeneration proceed, raising the question to what extent regeneration is a recapitulation of development. We address this by analyzing skeletal elements using a combination of micro-CT imaging, molecular profiling and clonal cell tracing. We find that, in contrast to development, regenerative skeletal growth is accomplished based entirely on cartilage expansion prior to ossification, not limiting the transversal cartilage expansion and resulting in bulkier skeletal parts. The oriented extension of salamander cartilage and bone appear similar to the development of basicranial synchondroses in mammals, as we found no evidence for cartilage stem cell niches or growth plate-like structures during neither development nor regeneration. Both regenerative and developmental ossification in salamanders start from the cortical bone and proceeds inwards, showing the diversity of schemes for the synchrony of cortical and endochondral ossification among vertebrates.

Diffuse PTH expression in parathyroid tumors argues against important functional tumor subclones.

Eur J Endocrinol.

2016 Feb 10

Haglund F, Juhlin CC, Kiss NB, Larsson C, Nilsson IL, HÖÖg A.
PMID: 26865585 | DOI: -

Abstract

OBJECTIVE:

Primary hyperparathyroidism is usually characterized by a monoclonal parathyroid tumor secreting excess parathyroid hormone (PTH). The main regulator of PTH secretion is calcium and the calcium-PTH set point is shifted in parathyroid tumor cells. We sought to investigate the relationship between tumor PTH and PTH mRNA expression and clinical presentation as well as regulatory factors including phosphate, vitamin D and fibroblast growth factor 23.

DESIGN:

A total of 154 parathyroid tumors were analyzed with PTH immunohistochemistry and chromogenic in situ hybridization of PTH mRNA. A subset of samples (n=34) was analyzed with quantitative real time PCR.

RESULTS:

Low tumor PTH mRNA was significantly associated with low tumor PTH immunoreactivity (P=0.026), but the two did not correlate with regard to histological distribution within individual tumors. Tumors displaying reduced PTH mRNA levels as compared with normal rim were significantly larger (P=0.013) and showed higher expression of the Calcium Sensing Receptor (P=0.046). Weaker tumor PTH mRNA was significantly associated with higher concentration of circulating 25-hydroxyvitamin D (P=0.005). No significant correlation was seen between PTH immunoreactivity and patient biochemistry. Tumor weight was strongly associated with circulatory concentrations of calcium and PTH.

CONCLUSIONS:

No areas with apparently higher PTH expression were identified, perhaps suggesting that hyperfunctioning parathyroid tumor subclones should be rare. Circulating 25-hydroxyvitamin D levels may influence tumor PTH expression in vivo. If PTH immunoreactivity reflects the tumor calcium-PTH set point, our data imply that the main determinant of disease severity should be tumor weight.

	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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Advanced Cell Diagnostics

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