Indiana University-Purdue University Indianapolis (IUPUI)Glucocorticoid excess is a leading cause of osteoporosis. The loss of bone mass
and strength corresponds to the increase in fractures exhibited after three months of
glucocorticoid therapy. Glucocorticoids induce the bone cellular responses of deceased
bone formation, increased osteoblast/osteocyte apoptosis, and transient increased bone
resorption, which result in rapid bone loss and degradation of bone microarchitecture.
The current standard of care for osteoporosis is bisphosphonate treatment;
however, these agents further suppress bone formation and increase osteonecrosis and
low energy atypical fracture risks. Thus, there is an unmet need for interventions that
protect from glucocorticoid therapy. The purpose of these studies was to investigate
novel mechanisms that potentially interfere with glucocorticoid-induced bone loss. We
chose to explore pathways that regulate endoplasmic reticulum stress, the canonical
Wnt pathway, and Pyk2 activity. Pharmacologic reduction of endoplasmic reticulum
stress through salubrinal administration protected against glucocorticoid-induced bone
loss by preservation of bone formation and osteoblast/osteocyte viability. In contrast,
inhibition of Wnt antagonist Sost/sclerostin and inhibition of Pyk2 signaling did not
prevent glucocorticoid-induced reductions in bone formation; however, both
Sost/sclerostin and Pyk2 deficiency protected against bone loss through inhibition of
increases in resorption. Overall, these studies demonstrate the significant contributions
of reductions in bone formation, increased osteoblast/osteocyte apoptosis, and
elevations in resorption to the rapid 6-12% bone loss exhibited during the first year of
glucocorticoid therapy.
However, glucocorticoid excess also induces skeletal muscle weakness, which is
not reversed by bisphosphonate treatment or the interventions reported here of salubrinal, Sost/sclerostin inhibition, or Pyk2 deficiency. Further, the novel finding of
increased E3 ubiquitin ligase atrophy signaling induce by glucocorticoids in both bone
and muscle, by tissue-specific upstream mechanisms, provides opportunities for
therapeutic combination strategies. Thus, future studies are warranted to investigate the
role of E3 ubiquitin ligase signaling in the deleterious glucocorticoid effects of bone and
muscle
