A role for autophagy in bone biology

Autophagy, which is a cellular process of macromolecular and organelle recycling, is now known to have an important role in bone biology. However, the exact task of autophagy in different types of bone cell remains unclear. Research by Reuben Kim and colleagues now begins to unravel the function of autophagy processes in bone.

Femurs from 6-month-old mice from Becn1 wild-type (left) and Becn1 cKO (right) mice, showing a thickening of the cortical bone but diminished trabecular bone mass in cKO mice. Image courtesy of Reuben Kim/UCLA School of Dentistry.

“In our study, we decided to use mice deficient in Beclin1 in osteoclasts (Becn1 cKO) because Beclin1 is an indispensable protein for autophagy initiation (for example, phagophore formation),” explains Kim. “We wanted to see what happened in the mice when autophagy gets blocked at the early stage during osteoclast differentiation.”

First, Kim and colleagues carried out in vitro experiments using primary bone-derived macrophages (BDMs, these cells are precursors of osteoclasts) obtained from mice and autophagy-reporter mouse macrophage cell lines. “It is well-known that receptor activator of NF-κB ligand (RANKL) plays a critical role in osteoclast differentiation,” says Kim. The researchers saw that RANKL induces autophagy during osteoclast differentiation. Moreover, Beclin1 overexpression increased osteoclast differentiation of reporter cells. Further examination of the function of Beclin1 in vitro revealed that TRAF6-dependent ubiquitination of Beclin1 is crucial for autophagy induction and osteoclast differentiation.

Importantly, Becn1 cKO mice showed increased cortical bone thickness in the femur but had decreased trabecular bone mass and quality compared with wild-type animals. Moreover, Becn1 cKO animals had impaired growth plate formation and chondrocyte differentiation. Ex vivo experiments of BDM showed that the bone-resorbing function of osteoclasts is decreased in Becn1 cKO mice.

“the bone-resorbing function of osteoclasts is decreased in Becn1 cKO mice”

“Targeting autophagy in osteoclasts would be a great strategic way to prevent pathologic bone loss; however, based on our findings, this strategy might come with a cost of inhibiting chondrocyte differentiation and long bone growth,” concludes Kim. “Our future studies will aim to develop ways of inhibiting autophagy in an osteoclast-specific manner.”