They later found that the Schnurri-3 gene product is required in osteoblasts—when selectively deleted in osteoblasts, you can recreate the phenotype—and that it seemed to be active at every stage of differentiation.
In a particularly exciting discovery, researchers found that knocking out Schnurri-3 resulted in a kind of decoupling of bone resorption and formation, running counter to the “dogma” that resorption and formation always go hand in hand.2
“We see very high bone formation in Schnurri-3 knockout animals, but we actually see reduced rates of bone resorption,” Dr. Glimcher said. Schnurri-3’s role in inhibiting bone resorption is related to its role in promoting RANK-ligand activity, she said.
“It turns out that Schnurri-3 is a co-activator of the key transcription factor called CREB that activates transcription of the RANK ligand gene,” she said. “Hence, in the absence of Schnurri-3, CREB is much less potent and you get lower levels of RANK ligand,” she said. “So that was a molecular answer to the question of how Schnurri-3 inhibits osteoclast activation.
“It is a fortunate event since we now have a gene whose silencing would result in both an increase in bone formation and at the same time inhibit bone resorption,” Dr. Glimcher said.
Researchers tested this further by inducing muscle paralysis in Schnurri-3 knockout mice, which would typically cause bone loss due to atrophy in normal mice. But in these mice, there was not only no bone loss, but bone continued to accumulate.
They then delved into the mechanisms and came away with these findings:
- Most of the activity of Schnurri-3 could be traced back to just a small portion of the molecule—to just three amino acids that sit within the D-domain, a binding site for a protein in the MAP kinase pathway, which controls bone mass.
- Within the D domain, Schnurri-3 represses the activity of ERK, extracellular-signal-regulated kinase, which leads to low bone mass.
- There is genetic interaction between Schnurri-3 and LRP5, a receptor that is mutated in some patients, causing low bone mass.
Dr. Glimcher acknowledged that predicting the effect of a therapy that reduces the activity of a gene vs. complete deletion of that gene can be tricky: “It is different than treating a patient with a drug, because when you’re treating a patient with a drug you’re not completely deleting that target from Day 0.” So they transiently inhibited Schnurri-3 in adult mice for six weeks and found that the levels were reduced by about 35%, and found that that was enough to have a positive impact on bone mass.
