Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice

Abstract

The transcription factor Osterix (Osx) is required for osteoblast differentiation and bone formation during embryonic development, but it is not known whether Osx has an essential function in postnatal bone growth and in bone homeostasis. Conditional deletion of Osx at several time points postnatally revealed that Osx was essential for osteoblast differentiation and new bone formation in growing and adult bones. Additionally, inactivation of Osx in bones severely disrupted the maturation, morphology, and function of osteocytes. These findings identify Osx as having an essential role in the cell-specific genetic program of osteocytes. Interestingly, Osx inactivation also led to the massive accumulation of unresorbed calcified cartilage in a large area below the growth plate of endochondral bones. This specific area was also marked by an unanticipated almost complete lack of bone marrow cells and a marked decrease in the density and size of osteoclasts. This diminished density of osteoclasts could contribute to the lack of resorption of mineralized cartilage. In addition, we speculate that the abnormally accumulated, mainly naked cartilage represents an unfavorable substrate for osteoclasts. Our study identifies Osx as an essential multifunctional player in postnatal bone growth and homeostasis.osteoblast differentiation | skeletal homeostasis | transcription factor | osteocyte | cartilage resorption T he identification of master transcription factors essential for osteoblast differentiation and bone formation during embryonic development has greatly advanced our knowledge of bone biology. However, the transcriptional control of postnatal bone formation and homeostasis remain poorly understood. Normal skeletal growth and homeostasis depends on the coordinated activities of three types of bone cells: osteoblasts, osteoclasts, and osteocytes. Factors secreted by the mesenchyme-derived osteoblasts also control the differentiation and activity of the boneresorbing osteoclasts derived from hematopoietic stem cells. Conversely, bone resorption by osteoclasts releases factors important for bone formation. Osteocytes, which make up over 90-95% of all bone cells in adult animals, are derived from mature osteoblasts and are embedded inside the bone matrix. It has been suggested that osteocytes are mediators of mechanical and hormonal stimulations to control the activity of both osteoblasts and osteoclasts (1). Osteocytes are regulators of mineralization and mineral homeostasis (2, 3), and by controlling Sost expression also act as modulators of Wnt signaling (4).Three transcription factors [β-catenin, Runx2, and Osterix (Osx)] are required for osteoblast differentiation and bone formation during embryonic development (5-9). Osx, which acts downstream of Runx2, is a zinc-finger-containing transcription factor essential for embryonic osteoblast differentiation and bone formation (8). During development, Osx is specifically expressed in osteoblast lineage cells and, at lower levels, in prehypertrophic chondrocytes, but not in ...

miR-93/Sp7 function loop mediates osteoblast mineralization

“…As a member of the Sp family of zinc fingercontaining transcription factors, Sp7 has been shown to be indispensable for the mineralization of osteoblasts in vivo. (21)(22)(23) Sp7-deficient mice only form cartilage without bone formation. (24) Moreover, Mikami and colleagues (25) have reported Sp7 expression level was consistent with the degree of mineralization.…”

RECENT RESEARCH ON THE GROWTH PLATE: Mechanisms for growth plate injury repair and potential cell-based therapies for regeneration

“…Osteogenic transcription factors, Runx2 and osterix, are well known to be essential for osteoblast differentiation during embryonic development (Komori et al 1997, Nakashima et al 2002, Day et al 2005 and during postnatal bone growth and homeostasis (Zhou et al 2010). In addition, increased osterix expression has been observed during bone fracture healing, and osterix overexpression can induce bone healing (Tu et al 2007, Xu et al 2009.…”

Development of the Endochondral Skeleton

“…Whereas RUNX2 deletion leads to a hypoplastic perichondrium, loss of OSX causes ectopic cartilage formation beneath a thickened perichondrium at the midshaft of long bones (where a bone collar normally forms), possibly because of a fate switch of progenitors from osteoblasts to chondrocytes (Nakashima et al 2002). Beyond its role in embryonic osteoblast differentiation, OSX is also critical for postnatal osteoblast and osteocyte formation and function (Zhou et al 2010).…”