Breaking up the bone breakdown

Although no cure exists for osteoporosis, researchers are working to outline the pathways behind the bone-deterioration process. A study recently published in the Journal of Biological Chemistry describes a new pathway involved in bone breakdown, offering novel targets for pharmaceutical interventions against osteoporosis.

Bone remodeling involves two cell types: osteoclasts that break down existing bone and osteoblasts that form new bone. Too many osteoclasts result in bone breakdown exceeding bone formation, weakening the bone structure. Osteoclastogenesis, the development of osteoclasts from their precursor cells, hematopoietic stem cells, is regulated by receptor activator of nuclear factor κB ligand, or RANKL. RANKL binds to its corresponding receptor and begins the differentiation process. The signaling pathways initiated by RANKL, however, are not well understood.

The research team lead by Byung-Soo Youn identified two novel proteins, progranulin, or PGRN, and PGRN-induced receptor-like protein during osteoclastogenesis, or PIRO, that are regulated by RANKL and are vital for osteoclast development. This study was a collaborative effort between Wonkwang University in Korea and OsteoNeuroGen, of which Youn is also the chief executive officer. Exposure of bone marrow cells to PGRN and RANKL resulted in dramatic formation of osteoclasts. Endogenous PGRN levels also increased with exposure time to RANKL. Furthermore, suppressing PGRN production reduced osteoclast formation. Together, these data support a role for PGRN is important in osteoclast differentiation and as a downstream target of RANKL.

The researchers next investigated the downstream targets of PGRN and discovered an uncharacterized gene whose expression increased 20-fold in the presence of PGRN. The researchers named the protein PGRN-induced receptor-like protein during osteoclastogenesis, or PIRO for short. Suppressing PGRN expression reduced PIRO expression. Moreover, when the bone-marrow cells were stimulated with RANKL, PGRN expression was highest at two days, and PIRO expression was highest at three days, suggesting sequential activation. These data reinforce the idea that PIRO is a downstream target of PGRN. Suppressing PIRO expression also markedly decreased the formation of osteoclasts, further supporting that PIRO is required for RANKL-induced osteoclast formation.

This study adds more details to the signaling pathways that underlie osteoclastogenesis. The findings support that after RANKL binds to its receptor, transcription of PGRN is initiated, and PGRN level increases. PGRN then triggers a second wave of signaling that leads to production of PIRO and ultimately results in the formation of osteoclasts. This study offers PGRN/PIRO as a potential therapeutic target for treating osteoporosis.

Maggie Kuo Maggie Kuo was an intern at ASBMB Today when she wrote this story. Today she is a writer at the American Physiological Society. She earned her Ph.D. in biomedical engineering at Johns Hopkins University.