Recent findings have identified the family with sequence similarity 102 member A (Fam102a) protein as a new factor influencing bone remodeling, which plays a role in managing the differentiation of both osteoclasts and osteoblasts. This discovery holds promise for creating new therapeutic approaches to combat osteoporosis. The research highlights Fam102a’s essential function in the nuclear transport of important transcription factors and regulatory proteins that are crucial to the intricate process of bone remodeling.
Bones are living tissues that form the structure of the human skeleton and are essential for facilitating movement. The strength and stability of bones rely on bone remodeling—a highly controlled process involving the formation of new bone and the breakdown of old or damaged bone, executed by the actions of osteoblasts and osteoclasts, respectively. If this remodeling process is disrupted, it can result in brittle bones and lead to serious health issues, including osteoporosis and fractures. Consequently, the study of bone remodeling processes has become a significant focus for researchers worldwide.
While numerous studies have highlighted the specific regulatory pathways for the differentiation of osteoclasts and osteoblasts, there is limited understanding of the shared factors that affect the formation of both cell types. To discover new factors and mechanisms that influence the differentiation of osteoclasts and osteoblasts, a research team led by Professor Tomoki Nakashima from the Faculty of Dentistry at the Institute of Science Tokyo (Science Tokyo), Japan, performed advanced genetic experiments using both mice and cultured cells. Their findings were published in Nature Communications on January 2, 2025.
Nakashima shared insights from their research, stating, “We began by thoroughly analyzing gene expression patterns in cells derived from mice with specific DNA sequence alterations. The gene expression profile in these cells showed that the Fam102a gene is crucial for the differentiation of both osteoclasts and osteoblasts when key transcription factors are absent.”
After uncovering the role of Fam102a in both osteoclast and osteoblast differentiation, the researchers aimed to further understand the molecular interactions that facilitate bone remodeling. They discovered that the Fam102a protein promoted osteoblast differentiation by influencing the expression of the Osterix protein through the localization of the runt-related transcription factor 2 (Runx2).
Additionally, Nakashima and colleagues conducted various genetic tests on mice lacking Fam102a to assess its significance in bone remodeling. Their observations indicated that Fam102a was essential for the differentiation of both osteoblasts and osteoclasts, and the absence of Fam102a led to a condition resembling osteoporosis in the mice, marked by reduced bone volume.
In follow-up experiments, the researchers utilized a co-immunoprecipitation assay to explore protein-protein interactions. Their analysis uncovered a notable connection between Fam102a and the karyopherin subunit alpha 2 (Kpna2), a protein responsible for transporting molecules through the nuclear membrane. This finding suggested that Fam102a relies on Kpna2 to regulate Runx2 activity during osteoblast differentiation.
Further gene expression analysis of osteoblasts without Fam102a revealed that recombination signal binding protein for immunoglobulin κ J region-like (Rbpjl) was significantly downregulated, confirming the involvement of the Fam102a-Rbpjl pathway in osteoblast differentiation.
In conclusion, this research sheds light on the mechanisms that control bone metabolism and enhances the understanding of bone remodeling. Nakashima emphasized the research’s potential implications, stating, “Our findings reveal vital molecular interactions in the bone remodeling process and may contribute to the development of new treatments for osteoporosis.”
