Role of prolyl hydroxylase domain proteins in bone metabolism

Wolf, David; Muralidharan, Aruljothi; Mohan, Subburaman

doi:10.1016/j.afos.2022.03.001

Cited by 4 publications

(4 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, both in vitro and in vivo results suggest that KSR2 and mTOR affect hypoxia but not Notch signaling genes. The anabolic effects of hypoxia signaling on bone mass and vasculature are well established ( Mohan and Kesavan, 2022 ; Shen et al, 2009 ; Wan et al, 2010 ; Wang et al, 2007b ; Wolf et al, 2022 ). Thus, whether the increased hypoxia signaling pathway observed in bones of Ksr2 KO mice contributes to the increased trabecular bone mass remains to be established.…”

Section: Discussionmentioning

confidence: 99%

Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity

Gomez

Rundle

Xing

et al. 2022

eLife

View full text Add to dashboard Cite

Pathological obesity and its complications are associated with an increased propensity for bone fractures. Humans with certain genetic polymorphisms at the kinase suppressor of ras2 (KSR2) locus develop severe early-onset obesity and type 2 diabetes. Both conditions are phenocopied in mice with Ksr2 deleted, but whether this affects bone health remains unknown. Here we studied the bones of global Ksr2 null mice and found that Ksr2 negatively regulates femoral, but not vertebral, bone mass in two genetic backgrounds, while the paralogous gene, Ksr1, was dispensable for bone homeostasis. Mechanistically, KSR2 regulates bone formation by influencing adipocyte differentiation at the expense of osteoblasts in the bone marrow. Compared with Ksr2’s known role as a regulator of feeding by its function in the hypothalamus, pair-feeding and osteoblast-specific conditional deletion of Ksr2 reveals that Ksr2 can regulate bone formation autonomously. Despite the gains in appendicular bone mass observed in the absence of Ksr2, bone strength, as well as fracture healing response, remains compromised in these mice. This study highlights the interrelationship between adiposity and bone health and provides mechanistic insights into how Ksr2, an adiposity and diabetic gene, regulates bone metabolism.

show abstract

Section: Discussionmentioning

confidence: 99%

Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity

Gomez

Rundle

Xing

et al. 2022

eLife

View full text Add to dashboard Cite

show abstract

“…The anabolic effects of hypoxia signaling on bone mass and vasculature is well established (Mohan and Kesavan, 2022; Shen et al, 2009; Wan et al, 2010; Y. Wang et al, 2007; Wolf et al, 2022). Thus, whether the increased hypoxia signaling pathway observed in bones of Ksr2 KO mice contributes to the increased trabecular bone mass remains to be established.…”

Section: Discussionmentioning

confidence: 99%

Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity

Gomez

Rundle

Xing

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Pathological obesity and its complications are associated with an increased propensity for bone fractures. Humans with certain genetic polymorphisms at the kinase suppressor of ras2 (Ksr2) locus develop severe early-onset obesity and type 2 diabetes (T2D). Both conditions are phenocopied in mice with Ksr2 deleted, but whether this affects bone health remains unknown. Here we studied the bones of global Ksr2 null mice and found that Ksr2 negatively regulates femoral, but not vertebral, bone mass in two genetic backgrounds, while the paralogous gene, Ksr1, was dispensable for bone homeostasis. Mechanistically, KSR2 regulates bone formation by influencing adipocyte differentiation at the expense of osteoblasts in the bone marrow. Compared with Ksr2’s known role as a regulator of feeding by its function in the hypothalamus, pair feeding and osteoblast-specific conditional deletion of Ksr2 reveals that Ksr2 can regulate bone formation autonomously. Despite the gains in appendicular bone mass observed in absence of Ksr2, bone strength, as well as fracture healing response remains compromised in these mice. This study highlights the interrelationship between adiposity and bone health and provides mechanistic insights into how Ksr2, an adiposity and diabetic gene, regulates bone metabolism.

show abstract

“…Many systemic and local growth factors regulate bone formation processes. At the molecular level, hypoxia signaling is identified as a key signaling pathway that plays a central role in the regulation of bone formation both during normal physiology and under disease conditions [ 15 ]. Among the prolyl hydroxylase domain proteins, PHD2 has been found to be expressed in high abundance in bone cells and disruption of Phd2 gene in bone cells result in severe skeletal phenotype [ 16 , 17 ].…”

Section: Hypoxia Signaling and Bone Formationmentioning

confidence: 99%

“…Endochondral ossification, occurring in the axial skeleton and the long bones, involves a more complex route with mesenchymal tissue transforming into a cartilage which is subsequently replaced by bone. During intramembranous and endochondral bone formation mechanisms, mesenchymal stem cells differentiate into osteoblasts and chondrocytes, respectively, by processes that are controlled by a complex transcriptional network that involves HIFs [ 15 ].…”

Section: Hypoxia Signaling and Bone Formationmentioning

confidence: 99%

Role of prolyl hydroxylase/HIF-1 signaling in vascular calcification

Negri

2022

Clinical Kidney Journal

View full text Add to dashboard Cite

Morbidity and mortality of CKD patients are largely associated with vascular calcification, an actively regulated process in which vascular smooth muscle cells (VSMCs) change into cells similar to osteocytes/chondrocytes known as trans differentiation. Cellular and systemic response to low oxygen (hypoxia) is regulated by the prolyl hydroxylase/HIF-1 pathway. Recent studies highlighted that hypoxia-mediated activation of HIF-1 induces trans-differentiation of VSMCs into bone-forming type through an increase in osteo-/chondrogenic genes. Inhibition of the HIF-1 pathway abolished osteochondrogenic differentiation of VSMCs. Hypoxia strongly enhanced elevated phosphate-induced VSMC osteogenic trans-differentiation and calcification. HIF-1 was shown to be essential for phosphate enhanced VSMC calcification. O2-dependent degradation HIF-1 is triggered by the prolyl hydroxylase domain proteins (PHD). Prolyl hydroxylase inhibitors, daprodustat and roxadustat, increase high phosphate-induced VC in VSMCs, stabilizing HIF-1α and activating the HIF-1 pathway in these cells. Whether the use of these PHD inhibitors to treat anemia in CKD patients will favor the development and progression of vascular calcification remains to be explored.

show abstract

Role of prolyl hydroxylase domain proteins in bone metabolism

Cited by 4 publications

References 91 publications

Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity

Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity

Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity

Role of prolyl hydroxylase/HIF-1 signaling in vascular calcification

Contact Info

Product

Resources

About