Present study explains that Osteoclast secretion SLIT3 plays an osteoprotective role by synchronously stimulating bone formation and inhibiting bone resorption, making it a potential therapeutic target for metabolic bone diseases
Bone is a highly dynamic tissue that continually undergoes changes and regeneration throughout adult life through a process called remodeling.
Coupling is the process that links bone resorption to the formation in a temporally and spatially coordinated manner within the remodeling cycle, and it has become clear that there are essential coupling factors involved in preserving bone balance.
As bone remodeling occurs in different parts of the skeleton asynchronously and at different times, locally generated and regulated activities compromise essential control mechanisms.
In the present study, we determined that osteoclast-derived SLIT3 stimulates the migration and proliferation of osteoblast lineages via the activation of β-catenin.
Several lines of evidence point to the critical roles of osteoclast-derived coupling factors in the regulation of osteoblast performance. Here, researchers used a fractionated secretomic approach and identified the axon-guidance molecule SLIT3 as a clastokine that stimulated osteoblast migration and proliferation by activating β-catenin.
SLIT3 also inhibited bone resorption by suppressing osteoclast differentiation in an autocrine manner. Mice deficient in SLIT3 or its receptor, Robo1, exhibited osteopenic phenotypes due to a decrease in bone formation and increase in bone resorption.
Mice lacking SLIT3 specifically in osteoclasts had low bone mass, whereas mice with either neuron-specific SLIT3 deletion or osteoblast-specific SLIT3 deletion had healthy bone mass, thereby indicating the importance of SLIT3 as a local determinant of bone metabolism.
In postmenopausal women, higher circulating SLIT3 levels were associated with increased bone mass. Notably, injection of a truncated recombinant SLIT3 markedly rescued bone loss after ovariectomy.
Thus, the results indicate that SLIT3 plays an osteoprotective role by synchronously stimulating bone formation and inhibiting bone resorption, making it a potential therapeutic target for metabolic bone diseases.
At last, the results of the current in vitro and animal experiments have demonstrated that the SLIT3 secreted by differentiated osteoclasts functions as a potent local determinant of bone mass that regulates both osteoclasts and osteoblasts.
Furthermore, the additional clinical data suggest the possible important role of SLIT3 in human bone health. The results of the current study may thus provide a molecular basis for the development of a therapeutic agent with combined antiresorptive and bone-forming activities.