The glycosaminoglycan-binding domain of PRELP acts as a cell type-specific NF-κB inhibitor that impairs osteoclastogenesis

Proline/arginine-rich end leucine-rich repeat protein (PRELP) is a glycosaminoglycan (GAG)- and collagen-binding anchor protein highly expressed in cartilage, basement membranes, and developing bone. We observed that PRELP inhibited in vitro and in vivo mouse osteoclastogenesis through its GAG-binding domain (^hbdPRELP), involving (a) cell internalization through a chondroitin sulfate- and annexin II-dependent mechanism, (b) nuclear translocation, (c) interaction with p65 nuclear factor κB (NF-κB) and inhibition of its DNA binding, and (d) impairment of NF-κB transcriptional activity and reduction of osteoclast-specific gene expression. ^hbdPRELP does not disrupt the mitogen-activated protein kinase signaling nor does it impair cell survival. ^hbdPRELP activity is cell type specific, given that it is internalized by the RAW264.7 osteoclast-like cell line but fails to affect calvarial osteoblasts, bone marrow macrophages, and epithelial cell lines. In vivo, ^hbdPRELP reduces osteoclast number and activity in ovariectomized mice, underlying its physiological and/or pathological importance in skeletal remodeling.