Laboratory studyCoordinate expression of BMP-2, BMP receptors and Noggin in normal mouse spine
Introduction
Signaling by BMPs requires binding of the BMP molecules (BMP-2, -4 and -7) to one of two types of serine-threonine BMP receptors (BMPRs), known as type 1 (1a and 1b) and type 2 BMPR.1 These receptors then phosphorylate intra-cellular proteins, including the Smads (Smad 1–5) to effect intracellular signaling and physiological responses.[2], [3], [4], [5] Therefore, BMPR expression is a prerequisite for biological action of BMP. An important growth factor related to BMP and BMPR is Noggin, a molecule that has been shown to antagonize the action of the BMPs.[6], [7], [8], [9] The coordinate expression of these positive and negative regulators of BMP signaling points to a potential regulatory mechanism for bone induction.
BMPs are involved in the morphogenesis and development of many organ systems. The expression of BMPR-1a or -1b has been reported during bone formation in fracture repair and pathological ectopic bone formation in spinal ligaments.[3], [5], [10] BMPs also play a key role in the development and growth of neurons, bone and cartilage, therefore, they may be important in the morphogenesis of spinal systems. There is also evidence from animal models that BMPs play a role in diseases characterised by mineralization of ligaments, including ossification of the anterior or posterior longitudinal ligament, ankylosing spondylitis, ossification of the ligamentum flavum and spinal spondylosis. However, there have been no reports published to date that show the distribution of BMP-2, BMPR or Noggin in normal animal models using whole spinal tissue.[11], [12], [13] Although previous reports have described aspects of spinal ossification, little is known about the molecular mechanisms that drive this event in spinal tissue.
Therefore, we used in situ hybridization to define the spatial expression profiles and localization of BMP-2, BMPRs, and Noggin in the whole spine of normal mice.
Section snippets
Histological preparation
Three-week-old male ddY mice were used, purchased from Nippon SLC Co. (Shizuoka, Japan) and housed in cages with free access to food and water for 1 week prior to sacrifice. Mice were sacrificed with diethyl ether.
Specimens were removed en bloc and fixed in 10% neutral buffered formalin. They were decalcified with 20% EDTA after washing with 0.1 mol/L phosphate-buffered saline (PBS). They were then dehydrated through graded ethanol, and embedded in paraffin. Sections of 4-μm thickness were
Expression of BMP-2
BMP-2 was moderately and broadly detected in bone marrow cells in vertebral bone in the cervical, thoracic and lumbar spine. It was weakly detected in chondrocytes, hyaline cartilage cells and fibrous cells in the intervertebral discs in the cervical, thoracic, and lumbar spine. This pattern of moderate staining was repeated in the neurons of the spinal cord and it was also weakly detected in fibrous cells in parts of the yellow ligament in the cervical, thoracic and lumbar spine (Fig. 1A, B).
Expression of BMPR-1a
Discussion
The expression and distribution of BMP-2, BMPR-1b and -2 was confined to bone marrow cells in vertebral bone, chondrocytes, hyaline cartilage cells and fibrous cells in the intervertebral discs and neurons of the spinal cord in the entire spine. BMPR-1a was expressed similarly in those cells, but only very weakly in the cervical spine. These results suggest the coordinate expression of BMP-2, BMPR-1b and -2 might be associated with the development of the spine. BMPR-1a and -1b share
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