Paget disease (PD) is a chronic disorder in which bones grow larger and become weaker than normal due to the hyperactivities in both osteoclasts and osteoblasts. The author group is the pioneer who discovered that significant fractions of PD patients express measles virus nucleocapsid protein (MVNP). Consistently, OCL-targeted MVNP expression develops PD-like pathology in mice. They also previously discovered that IGF1/Igf1 level was elevated in the OCLs from PD patients or MVNP transgenic mice. Interestingly, Igf1 in MVNP expressing OCLs is NECESSARY to induce PD in MVNP transgenic mice based on the Igf1 conditional knockout mouse studies. In this report, they initially examined the functions of osteocytes (OCys), which are the most abundant and long-lived cells in bone, in the persistence of bone legions in PD. They found histological abnormalities and increase in the RANKL level in OCys in MVNP mice in an Igf1 dependent manner. RANKL plays a key role in OCL formation. Next, they discovered the critical roles of Igf1 signaling cascade in RANKL production, OCL formation and bone resorption, utilizing the antibodies and siRNA suppressing the function of Igf1 or Igf1R. Finally, they demonstrated OCL-targeted Igf1 expression is SUFFICIENT to develop PD in mice. They generated a new mouse strain expressing Igf1 in OCLs without MVNP, and observed PD development in it. This study further deepened mechanistic understanding of PD.
