Csukasi Fabiana, Bosakova Michaela, Barta Tomas, Martin Jorge H, Arcedo Jesus, Barad Maya, Rico-Llanos Gustavo A, Zieba Jennifer, Becerra Jose, Krejci Pavel, Duran Ivan, Krakow Deborah
Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, United States.
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.
Front Cell Dev Biol. 2023 Jan 16;10:963389. doi: 10.3389/fcell.2022.963389. eCollection 2022.
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.
骨生成与脂肪生成之间平衡的改变是多种骨骼疾病的致病特征。临床上，骨骼中骨髓脂肪增多会损害活动能力并增加骨折风险，降低患者的生活质量。骨生成与脂肪生成之间平衡的分子机制尚未完全明确，但骨骼祖细胞分化途径的改变起着关键作用。我们最近证明，甲状旁腺激素（PTH）/甲状旁腺激素相关肽（PTHrP）控制雷帕霉素机制性靶点（mTOR）的抑制剂DEPTOR的水平，并且DEPTOR水平在不同的骨骼疾病中会发生改变。在此，我们表明甲状旁腺激素受体-1（PTH1R）的突变会改变两种不同骨骼遗传疾病中骨骼祖细胞的分化，并导致骨骼中脂肪或软骨的积累。从机制上讲，DEPTOR控制转录共激活因子TAZ（具有PDZ结合结构域的转录共激活因子）的亚细胞定位，TAZ是一种转录调节因子，可控制骨骼干细胞分化为骨细胞或脂肪细胞。我们表明，DEPTOR对TAZ定位的调节是通过控制Dishevelled2（DVL2）的磷酸化来实现的。根据营养物质的可用性，DEPTOR直接与PTH1R相互作用以调节PTH/PTHrP信号传导，或者它与TAZ形成复合物，以阻止TAZ转运至细胞核并因此抑制其转录活性。我们的数据表明DEPTOR是骨骼祖细胞分化中的关键分子；其在病理条件下的失调会导致异常的骨/脂肪平衡。
