Abstract
Bone is constantly formed and resorbed throughout life by coordinated actions of osteoblasts and osteoclasts. However, the molecular mechanisms involved in osteoblast function remain incompletely understood. Here we show, for the first time, that the peptidyl-prolyl isomerase PIN1 controls the osteogenic activity of osteoblasts. Pin1 null mice exhibited an age-dependent decrease in bone mineral density and trabecular bone formation without alteration in cortical bone. Further analysis identified a defect in BMP signaling in Pin1 null osteoblasts but normal osteoclast function. PIN1 interacted with SMAD5 and was required for the expression by primary osteoblasts of osteoblast specific transcription factors (CBFA1 and OSX), ECM (collagen I and OCN) and the formation of bone nodules. Our results thus uncover a novel aspect of the molecular underpinning of osteoblast function and identify a new therapeutic target for bone diseases.
Highlights
From the late stages of embryonic development throughout adult life, bone is precisely remodeled by the coordinated actions of two opposing type of cells, osteoblasts and osteoclasts
We present new evidence that PIN1 associates with SMAD5 and is required for the expression of osteoblast specific transcription factors and the formation of bone nodules in vitro
As seen (Fig. 1A, top), PIN1 was expressed in bone at a level comparable to that seen in freshly purified human eosinophils (+C, positive control)
Summary
From the late stages of embryonic development throughout adult life, bone is precisely remodeled by the coordinated actions of two opposing type of cells, osteoblasts and osteoclasts. Imbalance in the differentiation and/or function of either cell type will deregulate remodeling, leading to bone diseases such as osteoporosis or Paget’s disease [1]. Many genetic studies have clarified the molecular cascades controlling osteoclast differentiation and function. The molecular control of osteoblast differentiation and function is not fully understood. Osteoblast commitment and differentiation are regulated by BMPs and WNT signaling that control the sequential actions of CBFA1/(RUNX2 or OSF2) and Osterix (OSX), two osteoblast-specific transcription factors [2]. Once expressed, these transcription factors drive osteoblasts to synthesize and secrete bone extracellular matrix (ECM) including type I collagen, osteocalcin and bone sialoprotein
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