Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL/M-CSF signaling and osteoclast polarization

Abstract

The modeling and remodeling of bone requires activation and polarization of osteoclasts, achieved by reorganization of the cytoskeleton. Members of the Rho subfamily of small GTPases, including Cdc42, are known regulators of cytoskeletal components, but the role of these proteins in bone physiology and pathophysiology remains unclear. Here, we examined loss-of-function mice in which Cdc42 was selectively ablated in differentiated osteoclasts and gain-of-function animals wherein Cdc42Gap, a protein that inactivates the small GTPase, was deleted globally. Cdc42 loss-of-function mice were osteopetrotic and resistant to ovariectomy-induced bone loss, while gain-of-function animals were osteoporotic. Isolated Cdc42-deficient osteoclasts displayed suppressed bone resorption, while osteoclasts with increased Cdc42 activity had enhanced resorptive capacity. We further demonstrated that Cdc42 modulated M-CSF-stimulated cyclin D expression and phosphorylation of Rb and induced caspase 3 and Bim, thus contributing to osteoclast proliferation and apoptosis rates. Furthermore, Cdc42 was required for multiple M-CSF-and RANKL-induced osteoclastogenic signals including activation and expression of the differentiation factors MITF and NFATc1 and was a component of the Par3/Par6/atypical PKC polarization complex in osteoclasts. These data suggest that Cdc42 regulates osteoclast formation and function and may represent a promising therapeutic target for prevention of pathological bone loss.

Signaling Cascades Governing Cdc42-Mediated Chondrogenic Differentiation and Mensenchymal Condensation

“…Such findings prompt us to speculate that ossification deficiency in Cdc42 mutants could be the consequence of improper cartilage degradation caused by overexpansion and nonresorption of terminal hypertrophic chondrocytes.This notion has been supported by previous studies showing that accumulation of hypertrophic chondrocytes may contribute to delayed terminal maturation of chondrocytes and apoptosis in the chondro-osseous junction in Prx1Cre;Cdc42 fl/fl and Col2Cre;Cdc42 fl/fl long bones (Aizawa et al 2012;Suzuki et al 2015). Though a positive correlation between the decreased number of osteoclasts adjacent to chondrocytes and delayed mineralization formation has been found in Col2Cre;Cdc42 fl/fl long bones and Cdc42 indeed regulates osteoclast formation and function (Ito et al 2010;Suzuki et al 2015), whether osteoclasts are directly or indirectly involved in the malformation of cartilage and bone in Cdc42 mutants needs to be further studied.…”

“…Though a positive correlation between the decreased number of osteoclasts adjacent to chondrocytes and delayed mineralization formation has been found in Col2Cre;Cdc42 fl/fl long bones and Cdc42 indeed regulates osteoclast formation and function (Ito et al 2010;Suzuki et al 2015), whether osteoclasts are directly or indirectly involved in the malformation of cartilage and bone in Cdc42 mutants needs to be further studied.…”

miR-29 Promotes Murine Osteoclastogenesis by Regulating Osteoclast Commitment and Migration

“…CDC42 is a small GTPase that regulates actin remodeling, as well as cell cycle control and survival (51). Although not required for actin ring formation, CDC42 regulates the rate of formation, as well as cell polarization (52). CDC42 also regulates migration by controlling podosome turnover, and it is important for the movement of hematopoietic progenitors and macrophages toward chemotactic signals (53,54).…”

Role of CrkII Signaling in RANKL-Induced Osteoclast Differentiation and Function

“…NFATc1 is a master transcription factor that regulates several osteoclast-specific genes, including TRAP, osteoclast-associated receptor (OSCAR), and cathepsin K, to induce osteoclast differentiation and bone resorption (6)(7)(8). Furthermore, the Rho small GTPase signaling pathway has been identified as one of the essential pathways for osteoclast differentiation and function (9)(10)(11)(12).…”