Membrane Transport Proteins in Osteoclasts: The Ins and Outs

Abstract

During bone resorption, the osteoclast must sustain an extraordinarily low pH environment, withstand immense ionic pressures, and coordinate nutrient and waste exchange across its membrane to sustain its unique structural and functional polarity. To achieve this, osteoclasts are equipped with an elaborate set of membrane transport proteins (pumps, transporters and channels) that serve as molecular ‘gatekeepers’ to regulate the bilateral exchange of ions, amino acids, metabolites and macromolecules across the ruffled border and basolateral domains. Whereas the importance of the vacuolar-ATPase proton pump and chloride voltage-gated channel 7 in osteoclasts has long been established, comparatively little is known about the contributions of other membrane transport proteins, including those categorized as secondary active transporters. In this Special Issue review, we provide a contemporary update on the ‘ins and outs’ of membrane transport proteins implicated in osteoclast differentiation, function and bone homeostasis and discuss their therapeutic potential for the treatment of metabolic bone diseases.

New Insights Into Osteoclast Biology

“…Further matrix collagen (63) and extracellular acidosis (64) are also important factors driving fusion and resorption by osteoclasts at the bone surface. Although not critical to osteoclast survival, the capacity for osteoclasts to resorb bone via their specialized ruffled border is highly dependent on the process of membrane trafficking (65). Recent work has highlighted multiple novel osteoclastspecific therapeutic targets, which will inhibit their function rather than formation or survival, thereby negating possible feedback mechanisms such as those driving denosumab rebound bone loss, as discussed later.…”

Medication-Related Osteonecrosis of the Jaw: A Critical Narrative Review

“…These circumstances can modify the bone matrix by osteoclast reprogramming. These cells may produce an exacerbated number of osteolytic proteins such as H + -ATPases, V-ATPase, and chloride channel 7 [ 41 , 42 ]. This process alters natural homeostasis triggering acidification processes able to alter bone turnover [ 23 ].…”

Sugar transporter Slc37a2 regulates bone metabolism via a dynamic tubular lysosomal network in osteoclasts

“…Thus far, the molecular anatomy of SLs has largely been gleamed from unsystematic studies of genetically-modified mice with high bone mass phenotypes and incidental genetic findings arising from patients with rare sclerosing bone dysplasia (Sobacchi et al, 2013). While these studies have greatly advanced our understanding of the molecules involved in SL biogenesis (Lacombe et al, 2013) as well as the participants and downstream effectors regulating SL trafficking (Ng et al, 2019), surprisingly little is known about the nature and number of transport systems that reside on SLs and orchestrate the exchange of small molecules, such as ions, amino acids and sugars across its membrane (Ribet et al, 2021). In addition, how SLs are organized in osteoclasts, both spatially and temporally, is unclear.…”