The Evolving Role of PTH Signaling in Osteocytes

Over the past decade, advancements in cell line development and genetic tools have led to a wealth of new insights into the effects of parathyroid hormone (PTH), particularly on osteocytes-cells deeply embedded within the bone's mineral matrix. These cells were once believed to be inactive bystanders, with little, if any, role in skeletal and mineral homeostasis. This concept of passive osteocytes has been challenged in recent years and osteocytes are now recognized for their crucial functions in skeletal mechanotransduction, bone modeling and remodeling, mineral ion regulation, and hematopoiesis. Moreover, osteocytes are key targets of PTH, and studies utilizing genetically modified mice, in which the PTH receptor is either deleted or overexpressed, have shed light on the hormone's complex effects on these cells. Several signaling molecules, including salt kinase inhibitors and histone deacetylases, have been identified as part of PTH's intracellular signaling cascade. In addition to its effects on bone metabolism, PTH has also been implicated in regulating bone energy metabolism, skeletal aging, and hematopoiesis. This review summarizes both classical and emerging effects of PTH on osteocytes, highlights the limitations of current research, and offers perspectives for future investigations in the field.