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Molecular and cellular basis of bone resorption

Anatomy and biochemistry of the osteoclast

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Summary

Osteoclast research has an exciting history and a challenging future. More than 3 decades ago, it became evident that bone-resorbing osteoclasts are of hematopoietic origin and are ultimately linked to the “basic multicellular unit,” where they team up with the other cell types, including bone-forming osteoblasts. Since 2 decades, we have learned about the signaling pathways controlling genes relevant for osteoclastogenesis and bone resorption. It took another decade until the hypothesized “osteoclast differentiation” factor was discovered and was translated into an approved pharmacologic strategy. Here, the focus is on another molecular target, cathepsin K, a cysteine protease being released by the osteoclast into the resorption compartment. Genetic deletion and pharmacological blocking of cathepsin K reduces bone resorption but with ongoing bone formation. This observation not only holds great promise to become a new pharmacologic strategy, but it also provides new insights into the coordinated work of cells in the “basic multicellular unit” and thus, bridges the history and future of osteoclast research. This article is a short primer on osteoclast biology for readers of the special issue on odanacatib, a cathepsin K inhibitor.

Zusammenfassung

Die Erforschung der Osteoklasten hat eine interessante Historie und eine herausfordernde Zukunft. Vor mehr als drei Jahrzehnten wurde deutlich, dass die Osteoklasten hämatopoetischen Ursprungs sind und sich gemeinsam mit den anderen Zelltypen, einschließlich der knochenbildenden Osteoblasten, in der „Basic Multicellular Unit“, befinden. Seit zwei Jahrzehnten verdichtet sich das Wissen über die Signalwege zur Kontrolle der Osteoklastogenese und der Knochenresorption. Es dauerte ein weiteres Jahrzehnt bis der hypothetische „Osteoklasten-Differenzierungsfaktor“ entdeckt wurde der, in Folge, die Grundlage für eine zugelassene pharmakologische Strategie bildete. Ein anderes molekulares Ziel ist Cathepsin K, einem Cystein-Protease die vom Osteoklasten währen der Resorption freigesetzt wird. Genetische Deletion und pharmakologische Blockierung von Cathepsin K reduzieren die Knochenresorption, ohne Unterbrechung der Knochenneubildung. Dieses Prinzip hat das Potential eine neue pharmakologische Strategie zu werden und bietet neue Einblicke in die koordinierte Arbeit der Zellen in der „Basic Multicellular Unit“. Dieses Prinzip verbindet auch die Historie und Zukunft der Erforschung der Osteoklasten. Dieser Artikel ist ein kurzer Abriss der Osteoklastenbiologie für die Leser der Sonderausgabe zum Thema Odanacatib, einem Cathepsin-K-Inhibitor.

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  1. Laboratory of Oral Cell Biology, School of Dental Medicine, University of Bern, Freiburgstrasse 7, 3010, Bern, Switzerland

    Reinhard Gruber PhD

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Gruber, R. Molecular and cellular basis of bone resorption. Wien Med Wochenschr 165, 48–53 (2015). https://doi.org/10.1007/s10354-014-0310-0

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