Skeletal diseases caused by mutations in PTH1R show aberrant differentiation of skeletal progenitors due to dysregulation of DEPTOR

Fabiana Csukasi; Michaela Bosakova; Tomas Barta; Jorge H Martin; Jesus Arcedo; Maya Barad; Gustavo A Rico-Llanos; Jennifer Zieba; Jose Becerra; Pavel Krejci; Ivan Duran; Deborah Krakow

doi:10.3389/fcell.2022.963389

Skeletal diseases caused by mutations in PTH1R show aberrant differentiation of skeletal progenitors due to dysregulation of DEPTOR

Front Cell Dev Biol. 2023 Jan 16:10:963389. doi: 10.3389/fcell.2022.963389. eCollection 2022.

Authors

Fabiana Csukasi^{1

2

3}, Michaela Bosakova^{4

5

6}, Tomas Barta^{5

7}, Jorge H Martin¹, Jesus Arcedo², Maya Barad¹, Gustavo A Rico-Llanos^{2

3}, Jennifer Zieba¹, Jose Becerra^{2

3}, Pavel Krejci^{4

5

6}, Ivan Duran^{1

2

3}, Deborah Krakow^{1

7

8

9}

Affiliations

¹ Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, United States.
² Laboratory of Bioengineering and Tissue Regeneration (LABRET), Department of Cell Biology, Genetics and Physiology, University of Malaga, Institute of Biomedical Research in Malaga (IBIMA-Plataforma BIONAND), Malaga, Spain.
³ Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid, Spain.
⁴ Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.
⁵ Institute of Animal Physiology and Genetics of the CAS, Brno, Czechia.
⁶ International Clinical Research Center, St. Anne's University Hospital, Brno, Czechia.
⁷ Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czechia.
⁸ Department of Human Genetics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, United States.
⁹ Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, United States.

Abstract

Alterations in the balance between skeletogenesis and adipogenesis is a pathogenic feature in multiple skeletal disorders. Clinically, enhanced bone marrow adiposity in bones impairs mobility and increases fracture risk, reducing the quality of life of patients. The molecular mechanism that underlies the balance between skeletogenesis and adipogenesis is not completely understood but alterations in skeletal progenitor cells' differentiation pathway plays a key role. We recently demonstrated that parathyroid hormone (PTH)/PTH-related peptide (PTHrP) control the levels of DEPTOR, an inhibitor of the mechanistic target of rapamycin (mTOR), and that DEPTOR levels are altered in different skeletal diseases. Here, we show that mutations in the PTH receptor-1 (PTH1R) alter the differentiation of skeletal progenitors in two different skeletal genetic disorders and lead to accumulation of fat or cartilage in bones. Mechanistically, DEPTOR controls the subcellular localization of TAZ (transcriptional co-activator with a PDZ-binding domain), a transcriptional regulator that governs skeletal stem cells differentiation into either bone and fat. We show that DEPTOR regulation of TAZ localization is achieved through the control of Dishevelled2 (DVL2) phosphorylation. Depending on nutrient availability, DEPTOR directly interacts with PTH1R to regulate PTH/PTHrP signaling or it forms a complex with TAZ, to prevent its translocation to the nucleus and therefore inhibit its transcriptional activity. Our data point DEPTOR as a key molecule in skeletal progenitor differentiation; its dysregulation under pathologic conditions results in aberrant bone/fat balance.

Keywords: DEPTOR; PTH signaling; TAZ; Wnt; osteogenesis; skeletal differentiation.

Abstract

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