Loss of phosphatidylinositol-4-phosphate 5-kinase type-1 gamma (Pip5k1c) in mesenchymal stem cells leads to osteopenia by impairing bone remodeling


Bone is a solid bodily tissue made up of cells that are embedded in a dense extracellular matrix. Collagen and calcium phosphate are the two main components of this material that distinguish bone from other hard tissues like chitin, enamel, and shell. The individual bones of the human skeletal system and the skeletons of other vertebrates are made of bone tissue. Adult bone homeostasis requires bone remodeling. Bone formation and resorption are the two processes in the bone remodeling process. Maintaining bone mass and systemic mineral homeostasis requires a delicate balance between the two processes. The skeleton is a highly specialized and dynamic organ that regenerates regularly. The formation and maintenance of bone shape are accomplished through bone modeling. The acquisition of peak bone mass is the result of bone modeling. Bone modeling involves the removal of bone from one location and the formation of bone in other places. Even beyond skeletal maturity, the bone regeneration process continues with the periodic replacement of old bone with newly created bone in the same area, a process known as remodeling.

Bone remodeling is necessary for the repair of old and damaged bone caused by daily physical stress, as well as the prevention of aging effects and their consequences. Osteoporosis, a severe global health concern, is frequently caused by a disruption in the bone rebuilding process. The overall process of bone remodeling is well-coordinated and closely controlled, involving various cell types. The balance between bone production and resorption is required for physiological bone remodeling and systemic mineral homeostasis. Pip5k1c (phosphatidylinositol-4-phosphate 5-kinase type-1 gamma) is a lipid kinase that regulates receptor-mediated calcium signaling in numerous organs, but its function in the skeleton is unknown.

In a new research published in Journal of Biological Chemistry, Dr. Qinnan Yan, Dr. Huanqing Gao, Dr. Qing Yao, Dr. Guozhi Xiao from Southern University of Science and Technology together with Dr. Kun Ling from Mayo Clinic investigated Pip5k1c functions in skeletal development and homeostasis. The research team discovered that the deletion of Pip5k1c in MSC leads to low-turnover of osteopenia in adult mice. Loss of Pip5k1c inhibits osteoblast and bone formation through inactivating calcium/calmodulin-dependent protein kinase (CaMK) and downregulating Runx2 protein levels. The research work was done in great detail with elegant cellular and molecular techniques used as well as a genetic mouse model.

The authors showed that Pip5k1c loss in MSC promotes osteopenia in adult mice but not in fast-growing young mice. Pip5k1c deletion in MSC did not affect intramembranous or endochondral bone formation during skeletal development, which is noteworthy. They demonstrated that deletion of Pip5k1c from MSC produces low turnover of osteopenia in mice, with defects in osteoblast and bone production outnumbering those in osteoclast and bone resorption. Pip5k1c expression in MSC is required for osteoblast differentiation in bone, according to investigators. The deletion of Pip5k1c significantly lowers the number of osteoblast progenitors in the bone marrow and also mature osteoblasts on the surface of the bones. They further showed that the deletion of Pip5k1c causes Runx2 protein to be downregulated in BMSCs via inactivating CaMK2.

Furthermore, they showed that the Pip5k1c-CaMK2 signaling regulates the level of Runx2 protein in MSC and osteoblasts, revealing new information on Runx2 regulation and its involvement in bone mass control. Overexpression of the active CaMK2 increases the level of Runx2 protein, according to their observations. Additionally, they showed that the deletion of Pip5k1c in MSC significantly inhibits osteoclast production and bone resorption. Their co-culture investigations show that BMSC from cKO mice cannot maintain the wildtype osteoclasts differentiation from BMM effectively. Because Pip5k1c is not deleted in osteoclasts and their precursors, these finding shows that MSC loss alters the BM microenvironment.

In summary, researchers discovered that the loss of Pip5k1c inhibits bone marrow stromal cells ability to support osteoclast formation by bone marrow monocytes and lowers the osteoclast precursor population in bone marrow, resulting in decreased osteoclast formation and bone resorption. It can be concluded that Pip5k1c plays a vital role in bone mass regulation and that its ablation in MSC induces low-turnover osteopenia in mice via separate processes, suggesting that it could be a possible therapeutic approach for osteoporosis.


Yan Q, Gao H, Yao Q, Ling K, Xiao G. Loss of phosphatidylinositol-4-phosphate 5-kinase type-1 gamma (Pip5k1c) in mesenchymal stem cells leads to osteopenia by impairing bone remodeling. Journal of Biological Chemistry. 2022 Mar 1;298(3).

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