Cellular and molecular mechanisms of CCDC120-associated osteopetrosis - excessive bone resorption leads to low bone mass and bone erosion in many metabolic and degenerative bone diseases

The National Institute of Arthritis and Musculoskeletal and Skin Diseases awarded Southern California Institute For Research And Education $337,072 on June 19, 2026, under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846).

The award funds research into the cellular and molecular mechanisms of CCDC120-associated osteopetrosis, a novel form of X-linked osteopetrosis. The research examines how loss of the CCDC120 gene and its binding partner CYTOHESIN-2 in osteoclast precursors affects bone mass and osteoclast function. Pilot studies have demonstrated that genetic deletion of these factors results in high trabecular bone mass and defects in osteoclast cytoskeleton organization, which impairs osteoclast activation and bone resorption. The project investigates downstream molecular pathways and mechanisms to elucidate the pathogenesis of this rare osteopetrosis variant, which currently remains poorly understood despite identification of the causative genetic mutation in patients with no mutations in known osteopetrosis genes.

Work is performed in Long Beach, California, with a period of performance through March 31, 2031.

On the other hand, ablation of bone resorption due to either diminished osteoclastogenesis or impeded osteoclast function causes osteopetrosis, a group of genetically and clinically heterogenous diseases with aberrant high bone mass, deformities, and frequent fractures. Based on the mode of inheritance, osteopetrosis can be classified into the autosomal recessive osteopetrosis (ARO), the autosomal dominant osteopetrosis (ADO), and the X-linked osteopetrosis. In addition to bone disorders, most forms of osteopetrosis are associated with growth retardation and display hematologic, neurologic, and dental defects. The malignant infantile forms of osteopetrosis are lethal if left untreated. Thus, osteopetrosis is a group of life-threating osteoclast diseases with few treatment options. Although most (~90%) osteopetrosis-associated genes have been identified and functionally classified, there are still 10% of cases are orphans in that the mutated genes remain unknown. Recently, a hemizygous missense variant in the X-chromosome localized CCDC120 (coiled-coil domain containing 120) gene was identified in osteopetrosis patients who had no mutations in known osteopetrosis causal genes. Therefore, CCDC120-associated osteopetrosis represents a novel form of X-linked osteopetrosis. Nonetheless, the cellular and molecular mechanisms underlying the pathogenesis of CCDC120-associated osteopetrosis have not been elucidated. In our pilot studies, we have found that loss of CCDC120 and its binding partner cytohesin-2 (CYTH2) in osteoclast precursors in mice results in high trabecular bone mass and defects in osteoclast cytoskeleton organization, a prerequisite step in osteoclast activation and bone resorption. Moreover, genetic deletion of CYTH2 downstream substrate ARF1 causes similar cytoskeleton and bone resorption defects in osteoclasts. Based on our preliminary data and reports in literature, we hypothesize that CCDC120 regulates osteoclasts and bone homeostasis through its interaction with CYTH2 and subsequent activation of small gtpase ARF1 to promote actin polymerization at podosomes and at the sealing zone in osteoclasts. Loss or dysfunctions of CCDC120-CYTH2-ARF1 pathway retard osteoclast bone resorption and cause osteopetrosis in humans and rodent animals. To test our hypothesis, we will (a) determine the effects of CCDC120-deletion in osteoclasts on bone modeling/remodeling in mice and identify the molecular mechanisms by which CCDC120 regulates osteoclast cytoskeleton (AIM1). (B) define the osteoclast intrinsic role of CYTH2 in bone modeling/remodeling in mice and delineate the molecular mechanisms by which CYTH2 regulates osteoclast cytoskeleton (AIM2). (C) unravel the cell autonomous function of ARF1 in osteoclast lineage cells during skeleton modeling and remodeling and identify the mechanisms by which ARF1 regulates osteoclast cytoskeleton (AIM3). Successful accomplishment of the proposed work will not only fill in the knowledge GAP of CCDC120-associated osteopetrosis but also greatly advance osteoclast biology. Translationally, identification of the molecular mechanisms underlying the CCDC120-CYTH2-ARF1 pathway in osteoclasts may provide novel therapeutic targets for treatment of osteoporosis and other metabolic bone diseases.