Defective osteogenesis of the stromal stem cells predisposes CD18-null mice to osteoporosis

doi:10.1073/pnas.0409397102

Defective osteogenesis of the stromal stem cells predisposes CD18-null mice to osteoporosis

^*Department of Physiology, University of Maryland School of Medicine, Rockville, MD 20855; ^†Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, and ^¶Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; ^‡Mesenchymal Stem Cell Group, Division of Haematology, Institute of Medical and Veterinary Science, Adelaide 5000, South Australia, Australia; and ^§Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202

Edited by Darwin J. Prockop, Tulane University, New Orleans, LA (received for review December 17, 2004)

Abstract

Osteogenesis by the bone marrow stromal stem cells (BMSSCs) supports continuous bone formation and the homeostasis of the bone marrow microenvironment. The mechanism that controls the proliferation and differentiation of BMSSCs is not fully understood. Here, we report that CD18, a surface protein present primarily on hematopoietic cells, but not on differentiated mesenchymal cells, is expressed by the stromal stem cells and plays a critical role in the osteogenic process. Constitutive expression of CD18 on BMSSCs using a retroviral promoter significantly enhances bone formation in vivo, whereas genetic inactivation of CD18 in mice leads to defective osteogenesis due to decreased expression of the osteogenic master regulator Runx2/Cbfa1. The defective osteogenesis of the CD18-null BMSSCs can be restored by expressing full-length, but not cytoplasmic domain-truncated, CD18. Radiographic analyses with dual-energy x-ray absorptiometry and 3D microcomputed tomography show that mice lacking CD18 have decreased bone mineral density and exhibit certain features of osteoporosis. Altogether, this work demonstrates that CD18 functions critically in the osteogenesis of BMSSCs, and thus lack of CD18 expression in the leukocyte adhesion deficiency patients may predispose them to osteoporosis.

Footnotes

↵ ∥ To whom correspondence may be addressed. E-mail: lizhang{at}som.umaryland.edu or sshi{at}mail.nih.gov.
Author contributions: Y.M., S.G., M.R.A., C.C., T.E.U., Y.B., S.S., and L.Z. designed research; Y.M., M.M., S.G., M.R.A., C.C., T.E.U., Y.B., D.E., and A.K. performed research; Y.M., M.M., S.G., M.R.A., T.E.U., Y.B., D.E., S.S., and L.Z. analyzed data; and Y.M., S.S., and L.Z. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: BMD, bone mineral density; BMSSC, bone marrow stromal stem cells; CFU-F, colony-forming unit fibroblast; HSC, hematopoietic stem cell; KO, knockout.