Recently, a research team led by Associate Professor Huiling CAO from the Department of Biochemistry at the Southern University of Science and Technology (SUSTech) and the SUSTech Homeostatic Medicine Institute systematically uncovered the core mechanism by which the Ip6k2–Runx2 molecular axis regulates osteoclast differentiation and mediates coupling in bone remodeling. The study proposes a novel therapeutic strategy for osteoporosis by selectively inhibiting bone resorption through targeting Ip6k2 without impairing bone formation. The findings were published online in Nature Communications.

Osteoporosis is a highly prevalent metabolic skeletal disorder characterized by an imbalance between osteoblast and osteoclast activities, leading to excessive bone resorption, bone mass loss, and increased fracture risk. For a long time, the key transcription factor Runx2 has been recognized as a central regulator of osteoblast differentiation; however, its function in osteoclasts has not been fully elucidated.

The research team first confirmed, using multi-species transcriptomic datasets from both humans and mice, that Runx2 is highly expressed in osteoclast precursor cells. Through osteoclast precursor-specific conditional knockout mouse models (Lyz2-Cre) and in vitro osteoclast differentiation assays, they demonstrated that Runx2 directly binds to the promoter of cathepsin K (Ctsk) and activates its transcription, thereby driving osteoclast maturation and bone resorption. Deletion of Runx2 in osteoclasts significantly increased bone mass in mice and effectively alleviated bone loss.

The study further revealed that conditional deletion of Runx2 in mature osteoclasts/cortical bone cells (CTSK-Cre) impairs cortical bone formation, highlighting the dual regulatory role of Runx2 in both bone formation and resorption and indicating limitations in directly targeting Runx2 for therapy.

To overcome the challenge of Runx2’s dual functions, the team performed transcriptomic and druggability analyses and identified its interacting protein Ip6k2. Co-immunoprecipitation, colocalization assays, and transcriptional reporter analyses demonstrated that Ip6k2 directly interacts with Runx2 and specifically enhances its transcriptional activity in osteoclasts, thereby upregulating Ctsk expression. Knockdown of Ip6k2 reduced Runx2 protein levels and inhibited osteoclastogenesis through post-transcriptional regulation. Animal studies further confirmed that Runx2 and Ip6k2 function within the same linear regulatory pathway, establishing Ip6k2 as a specific regulator of Runx2-mediated osteoclast function.

Pharmacological validation using the selective Ip6k2 inhibitor UNC7467 in aged osteoporotic mice showed that continuous administration for six weeks increased bone mineral density by nearly 50%. Experiments using primary human cells further confirmed that UNC7467 selectively inhibited osteoclast differentiation without affecting the osteogenic potential of bone marrow mesenchymal stem cells.

Compared with existing Ctsk inhibitors, which are associated with cerebrovascular adverse effects, the Ip6k2-targeting strategy specifically downregulates Ctsk expression in a cell-type-specific manner, thereby avoiding systemic off-target toxicity. This pathway also provides a unified therapeutic target for multiple osteoporosis subtypes, including postmenopausal, age-related, and inflammation-induced osteoporosis.

This study is the first to define the Ip6k2–Runx2–Ctsk osteoclast-specific regulatory axis, breaking the limitation of bidirectional inhibition in conventional targets and enabling precise decoupling of bone remodeling processes. It provides a new molecular blueprint for the development of targeted therapeutics for osteoporosis.

The work was co-first authored by Dr. Guixing MA and Dr. Yong CHEN from the Department of Biochemistry at SUSTech, with Associate Professor Huiling CAO serving as the corresponding author. SUSTech is the first affiliated institution of the paper.

Paper Link: https://www.nature.com/articles/s41467-026-75098-2