Reprint of: The Great Beauty of the osteoclast

doi:10.1016/j.abb.2014.08.009

Archives of Biochemistry and Biophysics

Volume 561, 1 November 2014, Pages 13-21

https://doi.org/10.1016/j.abb.2014.08.009 Get rights and content

Highlights

•
Osteoclasts are multinucleated bone resorbing cells.
•
They have a tight link with the immune system.
•
They regulate hematopoiesis, bone formation and angiogenesis.
•
They activate the bone hormone osteocalcin by low pH-induced decarboxylation.

Abstract

Much has been written recently on osteoclast biology, but this cell type still astonishes scientists with its multifaceted functions and unique properties. The last three decades have seen a change in thinking about the osteoclast, from a cell with a single function, which just destroys the tissue it belongs to, to an “orchestrator” implicated in the concerted regulation of bone turnover. Osteoclasts have unique morphological features, organelle distribution and plasma membrane domain organization. They require polarization to cause extracellular bone breakdown and release of the digested bone matrix products into the circulation. Osteoclasts contribute to the control of skeletal growth and renewal. Alongside other organs, including kidney, gut, thyroid and parathyroid glands, they also affect calcemia and phosphatemia. Osteoclasts are very sensitive to pro-inflammatory stimuli, and studies in the ‘00s ascertained their tight link with the immune system, bringing about the question why bone needs a cell regulated by the immune system to remove the extracellular matrix components. Recently, osteoclasts have been demonstrated to contribute to the hematopoietic stem cell niche, controlling local calcium concentration and regulating the turnover of factors essential for hematopoietic stem cell mobilization. Finally, osteoclasts are important regulators of osteoblast activity and angiogenesis, both by releasing factors stored in the bone matrix, and secreting “clastokines” that regulate the activity of neighboring cells. All these facets will be discussed in this review article, with the aim of underscoring The Great Beauty of the osteoclast.

Section snippets

Osteoclast morphology and resorptive structures

There is no better way to describe an osteoclast than looking at its unusual shape (Fig. 1A and B): no other cell in the body has a similar morphology, nor such an impressive local digestive extracellular function.

Back in the ‘80s the osteoclast has been compared to an epithelial cell [1] for its ability to polarize and segregate unique plasma membrane domains [2]. In fact, an osteoclast presents a complex bone-facing membrane comprising an outer circular domain endowed with adhesion structures

Osteoclast polarization and bone resorption

Membrane polarization is a hallmark of mature resorbing osteoclasts and has the scope to arrange the cell to fulfill bone degradation. This is an extracellular event that cannot be accomplished by phagocytosis because bone is too broad to be degraded intracellularly. Fusion of mononuclear precursors to form multinucleated mature osteoclasts remarkably increases the cell size, but this is not enough to ensure intracellular degradation. Therefore, the biological solution is an extracellular

Control of calcemia and phosphatemia

For decades, the principal role of bone resorption, besides bone modeling and remodeling [3], was thought to be the control of calcemia and phosphatemia [53]. Although osteoclasts are “voracious” and very rapid in bone breakdown, their activity is not the only one in the body to increase calcemia and phosphatemia. Two lines of additional interventions impact the upkeep of hematic calcium and phosphate within normal ranges: (i) the contribution of a vast endocrine network which regulates gut

Osteoclast and the immune system

Osteoimmunology is a scientific neologism that describes the tight relationship between the skeleton and the immune system [58], [59]. It is not surprising that bone and immune cells talk to each other because lymphoid stemness arises in bone marrow [60], where both memory B-cells and T-cells are also located [61], [62]. Bone and bone marrow are now considered a single organ, with a hard bony cortex and a medullary parenchymal core intermingled with bony trabeculae, in which

Osteoclast functions beyond bone resorption

The view we had in the past of the osteoclast as a cell with one purpose, generated just to disrupt the tissue it belongs to, turned out to be wrong. It is now believed that osteoclasts is an “orchestrator” with further functions beyond bone resorption. A role in at least four major additional events is now known to be played by osteoclasts, consisting in the regulation of (i) hematopoiesis, (ii) bone formation, (iii) intraosseous angiogenesis, and (iv) hormonal functions of osteocalcin.

Osteoclasts as determinant of organismal homeostasis

The skeleton is now recognized to be central to the homeostasis of many peripheral organs. For instance, its endocrine functions through the FGF23 [53] and the osteocalcin pathways [118], [119], [120] are well described and confirmed to represent major routes of organismal regulation.

Osteoclasts have been demonstrated to contribute to the endocrine function of bone. In fact, osteocalcin is an important and specific osteoblast-derived protein that is stored in bone matrix in a highly

Conclusions

In this article we have underscored the canonical (bone resorption) and non-canonical (regulation of hematopoiesis, bone formation and angiogenesis, and contribution to the bone endocrine function) roles of osteoclasts. The peculiar morphology and immune nature make the osteoclast a cell of great interest. More must be discovered to fully understand their molecular pathways, signaling machineries and regulatory mechanisms, with the aim to exploit this knowledge to better elucidate the central

Acknowledgments

The original work was performed with the financial support from the European Union (Programme “PEOPLE” – Call identifier: FP7-PEOPLE-2011-IRSES Proposal No. 295181 – Acronym: INTERBONE, and “Collaborative Project – Large-scale integrating project” – Call identifier: FP7-HEALTH.2012.2.1.1-1-C Proposal No. 602300 – Acronym: SYBIL), the Associazione Italiana per la Ricerca sul Cancro (AIRC), and Telethon (Grant GGP09018) to A.T. We are indebted to Dr. Rita Di Massimo for manuscript editing.

References (121)

T. Domon et al.
Tissue Cell
(2002)
C. Supanchart et al.
Arch. Biochem. Biophys.
(2008)
F. Saltel et al.
Eur. J. Cell Biol.
(2008)
A. Del Fattore et al.
Arch. Biochem. Biophys.
(2008)
L.T. Duong et al.
Matrix Biol.
(2000)
S. Ory et al.
Eur. J. Cell Biol.
(2008)
H. Zhao et al.
Biochem. Biophys. Res. Commun.
(2002)
F.P. Coxon et al.
Semin. Cell Dev. Biol.
(2008)
J. Bertaud et al.
Acta Biomater.
(2010)
I.A. Silver et al.
Exp. Cell Res.
(1988)

A. Del Fattore et al.

Bone

(2008)

N. Mitić et al.

Arch. Biochem. Biophys.

(2005)

T.J. Sheu et al.

J. Biol. Chem.

(2003)

T.L. Andersen et al.

Bone

(2004)

H. Nakamura et al.

Bone

(2004)

P. Hou et al.

Bone

(2004)

K. Irie et al.

Tissue Cell

(2001)

A. Teti et al.

Bone

(2009)

T.D. Rachner et al.

Lancet

(2011)

B.S. Noble

Arch. Biochem. Biophys.

(2008)

F. Di Rosa et al.

Trends Immunol.

(2005)

M. Baud’huin et al.

Cytokine Growth Factor Rev.

(2013)

Z.S. Buchwald et al.

Bone

(2013)

S. Tatsumi et al.

Cell Metab.

(2007)

K. Thammasitboon et al.

Bone

(2006)

F. Di Virgilio

Trends Pharmacol. Sci.

(2007)

R.L. Porter et al.

Arch. Biochem. Biophys.

(2008)

O. Gurevitch et al.

Med. Hypotheses

(2006)

B.J. Frisch et al.

Blood

(2009)

S. Lymperi et al.

Blood

(2011)

Y. Takamatsu et al.

Blood

(1998)

R. Baron

Connect. Tissue Res.

(1989)

K.A. Szewczyk et al.

PLoS ONE

(2013)

B. Peruzzi et al.

Clin. Rev. Bone Miner. Metab.

(2012)

P.C. Marchisio et al.

J. Cell Biol.

(1984)

H. Schachtner et al.

Cytoskeleton (Hoboken)

(2013)

C.V. Gay et al.

Crit. Rev. Eukaryot. Gene Expr.

(2000)

S.L. Teitelbaum

Ann. N. Y. Acad. Sci.

(2011)

M. Mulari et al.

Microsc. Res. Tech.

(2003)

M.J. Hirvonen et al.

Bonekey Rep.

(2013)

R. Baron et al.

J. Cell Biol.

(1988)

G. Stenbeck et al.

J. Cell Sci.

(2004)

R. Baron et al.

J. Cell Sci.

(1990)

P.Y. Ng et al.

J. Bone Miner. Res.

(2013)

J. Vääräniemi et al.

J. Bone Miner. Res.

(2004)

A.Z. Zallone et al.

J. Anat.

(1983)

S.J. Hunter et al.

J. Histochem. Cytochem.

(1989)

H.C. Blair et al.

J. Cell Biol.

(1986)

S.H. Lee et al.

Nat. Med.

(2006)

L. Leisle et al.

EMBO J.

(2011)

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^☆: “The Great Beauty” is the English title of the movie “La Grande Bellezza” that won the 2014 Academy Award as best foreign film.

^☆☆: The Publisher apologies that this special issue paper was erroneously published in a regular issue. The article is reprinted here for the reader’s convenience and for the continuity of the special issue. For citation purposes, please use the original publication details; Archives of Biochemistry and Biophysics 558 (2014), pp. 70–78.

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ReviewReprint of: The Great Beauty of the osteoclast☆,☆☆

Highlights

Abstract

Section snippets

Osteoclast morphology and resorptive structures

Osteoclast polarization and bone resorption

Control of calcemia and phosphatemia

Osteoclast and the immune system

Osteoclast functions beyond bone resorption

Osteoclasts as determinant of organismal homeostasis

Conclusions

Acknowledgments

Tissue Cell

Arch. Biochem. Biophys.

Eur. J. Cell Biol.

Arch. Biochem. Biophys.

Matrix Biol.

Eur. J. Cell Biol.

Biochem. Biophys. Res. Commun.

Semin. Cell Dev. Biol.

Acta Biomater.

Exp. Cell Res.

Bone

Arch. Biochem. Biophys.

J. Biol. Chem.

Bone

Bone

Bone

Tissue Cell

Bone

Lancet

Arch. Biochem. Biophys.

Trends Immunol.

Cytokine Growth Factor Rev.

Bone

Cell Metab.

Bone

Trends Pharmacol. Sci.

Arch. Biochem. Biophys.

Med. Hypotheses

Blood

Blood

Blood

Connect. Tissue Res.

PLoS ONE

Clin. Rev. Bone Miner. Metab.

J. Cell Biol.

Cytoskeleton (Hoboken)

Crit. Rev. Eukaryot. Gene Expr.

Ann. N. Y. Acad. Sci.

Microsc. Res. Tech.

Bonekey Rep.

J. Cell Biol.

J. Cell Sci.

J. Cell Sci.

J. Bone Miner. Res.

J. Bone Miner. Res.

J. Anat.

J. Histochem. Cytochem.

J. Cell Biol.

Nat. Med.

EMBO J.

Review
Reprint of: The Great Beauty of the osteoclast☆,☆☆