Mesenchymal Stem Cells Differentiate Into Osteoblasts in Response to Inflammation

Koshiro Sonomoto¹, Kunihiro Yamaoka¹, Koichi Oshita¹, Shunsuke Fukuyo¹, Xiangmei Zhang², Kazuhisa Nakano³, Yosuke Okada¹ and Yoshiya Tanaka¹, ¹The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan, ²The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan, ³University of Occupational and Environmental Health, Kitakyushu, Japan

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: cytokines, mesenchymal stem cells and osteoblasts

Session Information

Title: Biology and Pathology of Bone and Joint

Session Type: Abstract Submissions (ACR)

Background/Purpose: Bone destruction due to enhanced osteoclast differentiation is a common observation in rheumatoid arthritis. It is well known that inflammatory cytokines cause osteoclatogenesis, however, the same cytokines also cause chronic enthesitis and excess abnormal bone formation as seen in ankylosing spondylitis. To elucidate the mechanism of this discrepancy, we herein investigated the effect of inflammation on osteoblastic differentiation property of mesenchymal stem cells (MSCs).

Methods: hMSCs were cultured in commercial osteogenic medium in the presence of inflammatory cytokines (TNF-α, IL-1β, IL-4, IL-6, IL-10 or IL-17) in vitro. Osteoblast differentiation was assessed by alkaline phosphates (ALP) staining and expression of osteoblastic markers and mineralization was evaluated by alizarin-red S staining.

Results: Inflammatory cytokines (TNF-α, IL-1β and IL-6) enhanced runt-related gene 2 (RUNX2) expression, ALP staining and mineralization. On the contrary, IL-4, IL-10 and IL-17 had no effect or slightly inhibited these markers. Among these cytokines, IL-1β most efficiently enhanced and promoted osteoblast differentiation, which is proved by expression of bone sialoprotein and osteocalcin. TNF-α, IL-1β and IL-6 did not alter the canonical wingless-type MMTV integration site (Wnt) signaling pathway but increase the expression of Wnt5a and its receptor, receptor tyrosine kinase-like orphan receptor 2 (Ror2), which are involved in non-canonical Wnt pathway, also known to possess important roles in osteoclastogenesis. siRNA of the Wnt5a or Ror2 completely inhibit enhanced osteoblast differentiation.

Conclusion: Inflammatory cytokines, which are well known to cause bone resorption by up-regulating osteoclast differentiation, also induced osteoblastogenesis of the hMSCs. This phenomenon indicates the involvement of MSCs in bone homeostasis under the circumstance of inflammation. Our data also indicates the quantitative or qualitative abnormality of MSCs can cause inadequate balance of bone resorption and bone formation.

Disclosure:

K. Sonomoto,
None;

K. Yamaoka,
None;

K. Oshita,
None;

S. Fukuyo,
None;

X. Zhang,
None;

K. Nakano,
None;

Y. Okada,
None;

Y. Tanaka,

Mitsubishi-Tanabe Pharma Corporation, Abbott Japan Co., Ltd., Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Santen Pharmaceutical Co., Ltd., Pfizer Japan Inc., Astellas Pharma Inc., Daiichi-Sankyo Co., Ltd., GlaxoSmithKlin,

Bristol-Myers Squibb, MSD K.K., Chugai Pharmaceutical Co., Ltd., Mitsubishi-Tanabe Pharma Corporation, Astellas Pharma Inc., Abbott Japan Co., Ltd., Eisai Co., Ltd. and Janssen Pharmaceutical K.K,

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