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The Journal of Bone and Joint Surgery (American) 85:13-18 (2003)
© 2003 The Journal of Bone and Joint Surgery, Inc.

Basic Science

Smad Signaling in Mesenchymal and Chondroprogenitor Cells

Yuji Hatakeyama, DDS, PhD, Jennifer Nguyen, BSc, Xibin Wang, PhD, Glen H. Nuckolls, PhD and Lillian Shum, PhD

Corresponding author: Lillian Shum, PhD
Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, 6 Center Drive, MSC 2745, Building 6, Room 324, Bethesda, MD 20892-2745. E-mail address: shuml{at}mail.nih.gov

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from National Institutes of Health Grant Z01 AR41114. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Abstract

Background: Bone morphogenetic proteins (BMPs) are pleiotropic differentiation factors that regulate cell fate determination by orchestrating the activities of downstream signal transducers. Although BMP ligands can elicit signal transduction from heterodimeric combinations of several type-I and type-II receptors, cytoplasmic transducers of the BMP signal include only three known BMP-specific regulatory Smad proteins: Smad1, 5, and 8. In order to determine the combination of signals that regulate chondrogenesis by BMPs, we analyzed the functions of BMP Smad subtypes.

Methods: Multipotential mesenchymal C3H10T1/2 cells and monopotential chondroprogenitor MC615 cells were placed in micromass culture in the presence or absence of BMP4. Chondrogenic differentiation was assayed by measuring Sox9 and type-II collagen gene expression and by alcian blue staining. Transactivation of type-II collagen by regulatory Smads singly, or in combination with Smad4, which partners with regulatory Smads, was assayed by luciferase activity.

Results: In the absence of BMP4, mesenchymal cells did not exhibit chondrogenic differentiation, whereas chondroprogenitor cells showed increased cartilage marker expression. In the presence of BMP4, the rate and extent of chondrogenesis increased in a dose-dependent manner for both cell types. We further determined that Smad1 or Smad5, but not Smad8, synergized with Smad4 in the transactivation of the type-II collagen promoter in chondroprogenitor cells. In contrast, Smad8 and Smad4 presented modest synergy in mesenchymal cells.

Conclusions: Taken together, our data suggest that uncommitted mesenchymal cells do not have the cellular competence to respond to the rate-limiting chondroinductive factor BMP. However, in chondroprogenitor cells, BMP stimulates differentiation through mechanisms mediated by Smad1 or Smad5 in combination with Smad4.

Clinical Relevance: Our functional studies of these mesenchymal and chondroprogenitor cells will establish the mechanisms of lineage commitment and provide a platform for molecular manipulations with predictable lineage outcome. Therefore, our knowledge base can provide the molecular basis for stem/progenitor cell differentiation and a paradigm for tissue engineering.


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