Sclerostin is a fundamentally important osteocyte-derived protein that inhibits bone formation. The downregulation of sclerostin (gene name Sost) in osteocytes mediates bone formation in response to mechanical and hormonal cues.
In this publication, Gould et al. (2021) use a mouse forelimb mechanical loading model to assess bone strains generated by ulnar loading and isolate proteins from these upper limbs for Western blotting analysis. Their data suggest that sclerostin abundance is regulated via post-translational modification in osteocytes to regulate bone formation, and that post-translational modification tags the protein to be degraded by lysosomes. These results reveal that osteocytes respond to mechanical and hormonal cues by redirecting the sclerostin protein from a secretory pathway to lysosomes for rapid degradation.
To further this research, this group assessed lysosomal degradation of sclerostin in iPSC-derived osteoblasts from Gaucher disease patients. These osteoblasts had significantly increased levels of sclerostin compared to iPSC-derived osteoblasts from healthy patients without Gaucher disease. To confirm this degradation pathway, they treated Gaucher iPSC-derived osteoblasts with recombinant GCase, which restored lysosomal function, and this treatment restored sclerostin abundance to control levels.
This publication provides key insights into the unexpected, rapid regulation of bone formation by sclerostin and reveals a new therapeutic target that can be exploited to improve bone mass in conditions such as osteoporosis, Gaucher disease, and other bone-degradation related diseases.