CRMP4 Inhibits Bone Formation by Negatively Regulating BMP and RhoA Signaling.

We identified the neuro-protein CRMP4 (collapsing response mediator protein-4) as a non-canonical osteogenic factor that regulating the differentiation of mouse bone marrow skeletal stem cells (bone marrow stromal stem cells, mBMSCs) into osteoblastic cells. CRMP4 is the only member of the CRMP 1-5 family to be expressed by mBMSCs and in osteoprogenitors of both adult mouse and human bones. In vitro gain and loss function of CRMP4 in murine stromal cells revealed its inhibitory effect on osteoblast differentiation. In addition, Crmp4 deficient mice (Crmp4(-/-) ) displayed 40% increase in bone mass, increased mineral apposition rate and bone formation rate, compared to wild type controls. Increased bone mass in Crmp4(-/-) mice was associated with enhanced BMP2 signaling and BMP2-induced osteoblast differentiation in Crmp4(-/-) osteoblasts (OBs). Furthermore, Crmp4(-/-) OBs exhibited enhanced activation of RhoA/focal adhesion kinase (FAK) signaling that led to cytoskeletal changes with increased cell spreading. In addition, Crmp4(-/-) OBs exhibited increased cell proliferation that was mediated via inhibiting cyclin-dependent kinase inhibitor 1B, p27(Kip1) and upregulating cyclin D1 expression that are targets of RhoA signaling pathway. Our findings identify CRMP4 as a novel negative regulator of osteoblast differentiation. This article is protected by copyright. All rights reserved.

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