Ostm1 from Mouse to Human: Insights into Osteoclast Maturation.

Jean Vacher,Monica Pata,Michael Bruccoleri

doi:10.3390/ijms21165600

Abstract

The maintenance of bone mass is a dynamic process that requires a strict balance between bone formation and resorption. Bone formation is controlled by osteoblasts, while osteoclasts are responsible for resorption of the bone matrix. The opposite functions of these cell types have to be tightly regulated not only during normal bone development, but also during adult life, to maintain serum calcium homeostasis and sustain bone integrity to prevent bone fractures. Disruption of the control of bone synthesis or resorption can lead to an over accumulation of bone tissue in osteopetrosis or conversely to a net depletion of the bone mass in osteoporosis. Moreover, high levels of bone resorption with focal bone formation can cause Paget’s disease. Here, we summarize the steps toward isolation and characterization of the osteopetrosis associated trans-membrane protein 1 (Ostm1) gene and protein, essential for proper osteoclast maturation, and responsible when mutated for the most severe form of osteopetrosis in mice and humans.

Highlights

Osteoclasts derive from hematopoietic stem cells that are shared with early myeloid lineage precursors
We showed that transcription levels of Acp5 and Ctsk were significantly enhanced in osteopetrosis associated trans-membrane protein 1 (Ostm1) cKO osteoclasts
Ostm1 is a negative modulator of cell multi-nucleation, an essential step toward cell maturation

Summary

Introduction

Osteoclasts derive from hematopoietic stem cells that are shared with early myeloid lineage precursors. The biochemical characterization of osteoclasts have been hampered by the fact that these giant cells are tightly attached to the bone matrix and are difficult to isolate As these cells are terminally differentiated and non-proliferative, a large number of cells have to be isolated at once. Our characterization of hematopoiesis in gl/gl mice was associated with mild anemia, a significant expansion of granulocyte-macrophage progenitors (CFU-GM) that give rise to osteoclasts and consistent with an increase of splenic CD11b+/Lys6-G+ monocytic cell subpopulation In addition to this myeloid defect, deregulation of lymphoid lineages in gl/gl mice resulted in a reduction of B cell populations and altered T cell distribution with thymus hypo-cellularity [44]. The presence of an inactive mature osteoclast population in these mice classified the gl/gl phenotype as an ‘osteoclast-rich’ osteopetrosis [46]

Mapping the gl Locus and Characterization of the Ostm1 Gene

Ostm1 in Osteoclast Maturation and Activation

OSTM1 and Human Osteopetrotic Patients

Findings

Concluding Remarks