CD44 Can Compensate for IgSF11 Deficiency by Associating with the Scaffold Protein PSD-95 during Osteoclast Differentiation

Abstract

Differentiation of osteoclasts, which are specialized multinucleated macrophages capable of bone resorption, is driven primarily by receptor activator of NF-κB ligand (RANKL). Additional signaling from cell surface receptors, such as cell adhesion molecules (CAMs), is also required for osteoclast maturation. Previously, we have demonstrated that immunoglobulin superfamily 11 (IgSF11), a member of the immunoglobulin-CAM (IgCAM) family, plays an important role in osteoclast differentiation through association with the scaffold protein postsynaptic density protein 95 (PSD-95). Here, we demonstrate that the osteoclast-expressed CAM CD44 can compensate for IgSF11 deficiency when cell–cell interaction conditions are suboptimal by associating with PSD-95. Impaired osteoclast differentiation in IgSF11-deficient (IgSF11−/−) cultures was rescued by antibody-mediated stimulation of CD44 or by treatment with low-molecular-weight hyaluronan (LMW-HA), a CD44 ligand. Biochemical analysis revealed that PSD-95, which is required for osteoclast differentiation, associates with CD44 in osteoclasts regardless of the presence or absence of IgSF11. RNAi-mediated knockdown of PSD-95 abrogated the effects of either CD44 stimulation or LMW-HA treatment on osteoclast differentiation, suggesting that CD44, similar to IgSF11, is functionally associated with PSD-95 during osteoclast differentiation. Taken together, these results reveal that CD44 can compensate for IgSF11 deficiency in osteoclasts through association with PSD-95.

Transcriptomics‐based analysis of the mechanism by which Wang-Bi capsule alleviates joint destruction in rats with collagen‐induced arthritis

“…The migration and maturation of osteoclasts and osteoblasts are important processes in bone remodeling. Pathways including “cell adhesion molecules”, “chemokine signaling pathway” and “gap junctions” all help to facilitate these processes [ 30 – 34 ]. “Complement and coagulation cascades” are seldom reported in the context of regulating bone remodeling in RA.…”

Synaptic Hyaluronan Synthesis and CD44-Mediated Signaling Coordinate Neural Circuit Development

“…It is interesting to speculate that this early localization to synapses may be necessary for initial stages of synaptogenesis. For example, HA binding can lead to clustering of CD44 [33], and CD44 is known to interact with and regulate the expression of post-synaptic density proteins, such as PSD-95 and Bassoon [31,63]. Thus, HA-CD44 interactions may help to initiate post-synaptic density (PSD) formation.…”

Plasma Membrane Receptors Involved in the Binding and Response of Osteoclasts to Noncellular Components of the Bone

“…Knockout of CD44 enhanced cell fusion in plastic but not in the bone. More recently, CD44 was shown to have a compensatory effect on knockout of immunoglobulin superfamily 11 (IgSF11), a calcium-dependent cell–cell adhesion molecule [ 112 ]. IgSF11 knockout mice were recently shown to have high bone mass.…”

“…IgSF11 knockout mice were recently shown to have high bone mass. The ability of CD44 to compensate for IgSF11 deficiency was apparently due to the interaction of both CD44 and IgSF11 with PSD-95, a scaffolding protein on the cytoplasmic face of cell adhesions [ 112 ]. These data suggest that, in osteoclasts, CD44, with its ability to interact with extracellular matrix ligands, might also interact with cell–cell adhesion molecules such as IgSF11 in the coordination of matrix binding and cell fusion.…”