The study investigates the cellular sources of RANKL, a key cytokine for osteoclast formation, during bone growth and remodeling. Using conditional mouse models and Cre-deleter strains, the researchers found that hypertrophic chondrocytes and osteocytes, both embedded in the matrix, are essential for RANKL production. Specifically, hypertrophic chondrocytes supply RANKL during bone growth, while osteocytes are crucial for bone remodeling. Deletion of RANKL in osteocytes leads to increased bone mass and protection from bone loss due to unloading. In contrast, RANKL produced by osteoblasts or their progenitors does not contribute to bone remodeling. These findings suggest that the rate-limiting step of matrix resorption is controlled by cells embedded within the matrix itself, providing new insights into the mechanisms of bone resorption and remodeling.The study investigates the cellular sources of RANKL, a key cytokine for osteoclast formation, during bone growth and remodeling. Using conditional mouse models and Cre-deleter strains, the researchers found that hypertrophic chondrocytes and osteocytes, both embedded in the matrix, are essential for RANKL production. Specifically, hypertrophic chondrocytes supply RANKL during bone growth, while osteocytes are crucial for bone remodeling. Deletion of RANKL in osteocytes leads to increased bone mass and protection from bone loss due to unloading. In contrast, RANKL produced by osteoblasts or their progenitors does not contribute to bone remodeling. These findings suggest that the rate-limiting step of matrix resorption is controlled by cells embedded within the matrix itself, providing new insights into the mechanisms of bone resorption and remodeling.