Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein.

Nicole R Gould,Marcus Hughes,Joseph P Stains,Manasa P Srikanth,Ricardo A Feldman,Christopher W Ward,Jenna M Leser,Katrina M Williams,James S Lyons,Olivia M Torre,Humberto C Joca,Ramzi J Khairallah

doi:10.7554/elife.64393

Nicole R Gould, Marcus Hughes + Show 10 more

Open Access

https://doi.org/10.7554/elife.64393

Copy DOI

Journal: eLife	Publication Date: Mar 29, 2021
Citations: 23	License type: CC BY 4.0

Affiliation: University of Maryland, Baltimore

Abstract

The downregulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation of the Sost gene hours after stimulation. Using mouse models and rodent cell lines, we describe the rapid, minute-scale post-translational degradation of sclerostin protein by the lysosome following mechanical load and PTH. We present a model, integrating both new and established mechanically and hormonally activated effectors into the regulated degradation of sclerostin by lysosomes. Using a mouse forelimb mechanical loading model, we find transient inhibition of lysosomal degradation or the upstream mechano-signaling pathway controlling sclerostin abundance impairs subsequent load-induced bone formation by preventing sclerostin degradation. We also link dysfunctional lysosomes to aberrant sclerostin regulation using human Gaucher disease iPSCs. These results reveal how bone anabolic cues post-translationally regulate sclerostin abundance in osteocytes to regulate bone formation.

Highlights

IntroductionThe down regulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH)
To establish the relevance of a load-induced loss of sclerostin protein in vivo, we examined if this rapid loss of sclerostin abundance, as determined by western blot or sclerostin immunofluorescence in sectioned bone, occurred following an acute bout of ulnar loading
Sclerostin protein abundance was rapidly reduced and calmodulin-dependent kinase II (CaMKII) activated in loaded versus contralateral non-loaded limbs (Figure 1D), and the percent of sclerostin positive osteocytes was decreased in loaded limbs versus contralateral non-loaded limbs (Figure 1 - supplement 1A), establishing that rapid sclerostin protein loss occurs in vivo following a single bout of mechanical stimulus

Summary

Introduction

The down regulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). Using mouse models and rodent cell lines, we describe the rapid, minutes-scale posttranslational degradation of sclerostin protein by the lysosome following mechanical load and PTH. We present a model, integrating both new and established mechanically- and hormonallyactivated effectors into the regulated degradation of sclerostin by lysosomes. Using a mouse forelimb mechanical loading model, we find transient inhibition of lysosomal degradation or the upstream mechano-signaling pathway controlling sclerostin abundance impairs subsequent loadinduced bone formation by preventing sclerostin degradation. We link dysfunctional lysosomes to aberrant sclerostin regulation using human Gaucher disease iPSCs. We link dysfunctional lysosomes to aberrant sclerostin regulation using human Gaucher disease iPSCs These results reveal how bone anabolic cues post-translationally regulate sclerostin abundance in osteocytes to regulate bone formation

Methods

Results

Conclusion