Abstract
Calcium (Ca2+) plays an important role in regulating the differentiation and function of osteoclasts. Calcium oscillations (Ca oscillations) are well-known phenomena in receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption via calcineurin. Many modifiers are involved in the fine-tuning of Ca oscillations in osteoclasts. In addition to macrophage colony-stimulating factors (M-CSF; CSF-1) and RANKL, costimulatory signaling by immunoreceptor tyrosine-based activation motif-harboring adaptors is important for Ca oscillation generation and osteoclast differentiation. DNAX-activating protein of 12 kD is always necessary for osteoclastogenesis. In contrast, Fc receptor gamma (FcRγ) works as a key controller of osteoclastogenesis especially in inflammatory situation. FcRγ has a cofactor in fine-tuning of Ca oscillations. Some calcium channels and transporters are also necessary for Ca oscillations. Transient receptor potential (TRP) channels are well-known environmental sensors, and TRP vanilloid channels play an important role in osteoclastogenesis. Lysosomes, mitochondria, and endoplasmic reticulum (ER) are typical organelles for intracellular Ca2+ storage. Ryanodine receptor, inositol trisphosphate receptor, and sarco/endoplasmic reticulum Ca2+ ATPase on the ER modulate Ca oscillations. Research on Ca oscillations in osteoclasts has still many problems. Surprisingly, there is no objective definition of Ca oscillations. Causality between Ca oscillations and osteoclast differentiation and/or function remains to be examined.
Highlights
Calcium (Ca2+) is a simple molecule, but has various cellular functions [1]
Our group showed that a rheumatic drug, cytotoxic T-lymphocyte antigen 4 (CTLA4)Ig, inhibits osteoclastogenesis by interfering with Ca2+ signaling via FcRγ, representing the first report of a cofactor that affects costimulatory signals during osteoclast differentiation [21]
Recent studies showed that the balance and the strength of costimulatory signals producing optimal Ca oscillations are important
Summary
Calcium (Ca2+) is a simple molecule, but has various cellular functions [1]. It acts as a common second messenger in many biological process [2,3]. Nuclear factor of activated T-cells 1 (NFATc1) is a master regulator gene for osteoclastogenesis [8]. Siglec-15, a receptor associated with DAP12, regulates osteoclast differentiation [27], and Siglec-15deficient mice show osteopetrosis [28]. In contrast to DAP12 and its coupling receptors, the role of FcRγ in osteoclastogenesis is ambiguous and environmentally dependent. Our group showed that a rheumatic drug, cytotoxic T-lymphocyte antigen 4 (CTLA4)Ig, inhibits osteoclastogenesis by interfering with Ca2+ signaling via FcRγ, representing the first report of a cofactor that affects costimulatory signals during osteoclast differentiation [21]. The costimulatory signals through FcRγ are complicated and environment-dependent It remains to be solved why the downstream mechanisms including Ca oscillations differ according to ITAM types
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