Abstract
Excessive bone resorption by osteoclasts (OCs) can result in serious clinical outcomes, including bone loss that may weaken skeletal or periodontal strength. Proper bone homeostasis and skeletal strength are maintained by balancing OC function with the bone-forming function of osteoblasts. Unfortunately, current treatments that broadly inhibit OC differentiation or function may also interfere with coupled bone formation. We therefore identified a factor, the purinergic receptor P2X5 that is highly expressed during the OC maturation phase, and which we show here plays no apparent role in early bone development and homeostasis, but which is required for osteoclast-mediated inflammatory bone loss and hyper-multinucleation of OCs. We further demonstrate that P2X5 is required for ATP-mediated inflammasome activation and IL-1β production by OCs, and that P2X5-deficient OC maturation is rescued in vitro by addition of exogenous IL-1β. These findings identify a mechanism by which OCs react to inflammatory stimuli, and may identify purinergic signaling as a therapeutic target for bone loss-related inflammatory conditions.
Highlights
Osteoclasts (OCs) are hematopoietic-derived cells that resorb bone and are required to maintain proper bone homeostasis and skeletal strength by balancing the bone-forming function of osteoblasts (OBs)
Monocytes were cultured with either MCSF + RANKL to differentiate toward the OC lineage, or IL-3 + IL-4 to generate multinucleated giant cells (MGCs), which undergo cell fusion
Expression of P2rx[5] was found significantly increased in both sorted OC4N and MGC4N populations compared to baseline BMM2N expression, but increased expression was not observed in 2N populations sorted from STAT6−/− bone marrow macrophages (BMMs) or MGC cultures (Fig. 1A)
Summary
Osteoclasts (OCs) are hematopoietic-derived cells that resorb bone and are required to maintain proper bone homeostasis and skeletal strength by balancing the bone-forming function of osteoblasts (OBs). A better treatment strategy may be to target late-stage OC biological processes (so-called “OC maturation”) in favor of early OC differentiation with the goal of inhibiting OC resorption without preventing secreting activities that contribute to productivebone formation In this regard, recent clinical trials of the selective cathepsin K inhibitor odanacatib, which targets OCresorption, showed inhibited bone resorption without diminution of either OC generation/survival or coupled bone formation[7, 8]. A single nucleotide polymorphism (SNP) found in the 3’ splice site of human P2rx[5] exon 10 in the majority of the population results in a truncated form of the P2X5 protein that lacks parts of both the ATP-binding domain and the second transmembrane domain[22, 23] While it remains unclear, from a population perspective, to what extent P2X5 regulates human physiology, the results we report here may still point to purinergic signaling, broadly, as a promising target for selectively inhibiting inflammatory bone loss
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