Calreticulin inhibits inflammation‐induced osteoclastogenesis and bone resorption

Abstract

Osteoclasts play key roles in bone remodeling and pathologic osteolytic disorders such as inflammation, infection, bone implant loosening, rheumatoid arthritis, metastatic bone cancers, and pathological fractures. Osteoclasts are formed by the fusion of monocytes in response to receptor activators of NF-κB-ligand (RANKL) and macrophage colony stimulating factor 1 (M-CSF). Calreticulin (CRT), a commonly known intracellular protein as a calcium-binding chaperone, has an unexpectedly robust anti-osteoclastogenic effect when its recombinant form is applied to osteoclast precursors in vitro or at the site of bone inflammation externally in vivo. Externally applied Calreticulin was internalized inside the cells. It inhibited key pro-osteoclastogenic transcription factors such as c-Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1)-in osteoclast precursor cells that were treated with RANKL in vitro. Recombinant human Calreticulin (rhCRT) inhibited lipopolysaccharide (LPS)-induced inflammatory osteoclastogenesis in the mouse calvarial bone in vivo. Cathepsin K molecular imaging verified decreased Cathepsin K activity when rhCalreticulin was applied at the site of LPS application in vivo. Recombinant forms of intracellular proteins or their derivatives may act as novel extracellular therapeutic agents. We anticipate our findings to be a starting point in unraveling hidden extracellular functions of other intracellular proteins in different cell types of many organs for new therapeutic opportunities. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2658-2666, 2017.

Calreticulin Blockade Attenuates Murine Acute Lung Injury by Inducing Polarization of M2 Subtype Macrophages

“…However, contradictory to the proinflammatory role of CALR, recent reports also showed that CALR may have an anti-inflammatory function in other animal models. For example, Fischer et al recently reported that recombinant human CALR can inhibit lipopolysaccharide (LPS)induced inflammatory osteoclastogenesis in the mouse calvarial bone (35). Another report indicated that intraperitoneal injection of recombinant CALR fragment 39-272 (CRT/39-272) into animal model with experimental autoimmune encephalomyelitis (EAE) can significantly reduce the disease severity of EAE (36).…”

Downregulation of Calreticulin and Annexin A2 in Cholesteatoma by 2-DE Analysis

“…CRT is also an endoplasmic reticulum chaperone and is involved in endoplasmic reticulum stress to prevent protein unfolding, but is downregulated in cholesteatoma. Fischer et al (35) reported that CRT inhibited lipopolysaccharideinduced inflammatory osteoclastogenesis and bone resorption. With the lytic enzymes and cytokines produced in cholesteatoma, the inflammatory condition may further promote epithelial proliferation in cholesteatoma.…”

Role of Cachexia and Fragility in the Patient Candidate for Cardiac Surgery

“…In addition, because in aged people the calcium homeostasis is usually altered, changes in calcium signaling and/or binding proteins have been proven to be effective markers of cellular and tissue dysfunction in these patients. The three "calcium homeostasis" biomarkers of fragility are S100B (S 100 calcium binding protein B) [84]; SMP30 (senescence-marker protein 30) [85]; calreticulin (a multifunctional protein initially identified as a Ca 2+ storage protein) [86]. Both regucalcin and calreticum reached high priority.…”