PTHrP and skeletal development

Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.31). 05/2006; 1068:1-13. DOI: 10.1196/annals.1346.002
Source: PubMed

ABSTRACT Parathyroid hormone-related protein (PTHrP) participates in the regulation of endochondral bone development. After the cartilage mold is established in fetal life, perichondrial cells and chondrocytes at the ends of the mold synthesize PTHrP. This ligand then acts on PTH/PTHrP receptors on chondrocytes. As chondrocytes go through a program of proliferation and then further differentiation into post-mitotic, hypertrophic chondrocytes, PTHrP action keeps chondrocytes proliferating and delays their further differentiation. Indian hedgehog (Ihh) is synthesized by chondrocytes that have just stopped proliferating and is required for synthesis of PTHrP. The feedback loop between PTHrP and Ihh serves to regulate the pace of chondrocyte differentiation and the sites at which perichondrial cells first differentiate into osteoblasts. Activation of the PTH/PTHrP receptor leads to stimulation of both Gs and Gq family heterotrimeric G proteins. Genetic analyses demonstrate that Gs activation mediates the action of PTHrP to keep chondrocytes proliferating, while Gq activation opposes this action. Downstream from Gs activation, synthesis of the cyclin-cdk inhibitor, p57, is suppressed, thereby increasing the pool of proliferating chondrocytes. PTHrP's actions to delay chondrocyte differentiation are mediated by the phosphorylation of the transcription factor, SOX9, and by suppression of synthesis of mRNA encoding the transcription factor, Runx2. These pathways and undoubtedly others cooperate to regulate the pace of differentiation of growth plate chondrocytes in response to PTHrP.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Radiation-induced complications in bone and cartilage are of increasing concern due to potential long-term effects in cancer survivors. Healthy articular cartilage may be exposed to radiation during either chondrosarcoma treatment or in-field radiotherapy of tumors located in close proximity to articulation. Cartilage exposed to radiation undergoes bone differentiation and senescence, which can lead to painful and disabling sequelae that can impair patient quality of life. An understanding of the biological processes involved in healthy cartilage response to radiotherapy may not only optimize the delivery of therapeutic radiation but also reduce the risk of long-term sequelae in irradiated cartilage. Over the last few decades, radiobiology studies have focused primarily on signaling and repair of DNA damage pathways induced by ionizing radiation in immortalized cells under conditions dramatically different from human homeostasis. This research needs to be continued and broadened, since the range of normal tissue responses to radiation exposure is still not fully understood, despite being recognized as the major limiting factor in the rupture of tissue homeostasis after radiotherapy. Human articular cartilage is an avascular tissue with low intracellular oxygen levels and is comprised of a single cell lineage of chondrocytes embedded in a highly dense and structured extracellular matrix. These relatively unique features may impact inherent cell radiation sensitivity and suggests that canonical cell responses to ionizing radiation may not be applicable to articular cartilage. Despite the number of studies in this field, radiation-induced modifications of chondrocyte proteome remain unclear because of the dramatic variability in reported experimental conditions. In this review, we propose to introduce cartilage tissue physiology and microenvironment concepts, and then present a comprehensive synthesis of cartilage radiation biology.
    Radiation Research 01/2015; DOI:10.1667/RR13928.1 · 2.70 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lizards capable of caudal autotomy exhibit the remarkable ability to “drop” and then regenerate their tails. However, the regenerated lizard tail (RLT) is known as an “imperfect replicate” due to several key anatomical differences compared to the original tail. Most striking of these “imperfections” concerns the skeleton; instead of the vertebrae of the original tail, the skeleton of the RLT takes the form of an unsegmented cartilage tube (CT). Here we have performed the first detailed staging of skeletal development of the RLT CT, identifying two distinct mineralization events. CTs isolated from RLTs of various ages were analyzed by micro-computed tomography to characterize mineralization, and to correlate skeletal development with expression of endochondral ossification markers evaluated by histology and immunohistochemistry. During early tail regeneration, shortly after CT formation, the extreme proximal CT in direct contact with the most terminal vertebra of the original tail develops a growth plate-like region that undergoes endochondral ossification. Proximal CT chondrocytes enlarge, express hypertrophic markers, including Indian hedgehog (Ihh), apoptose, and are replaced by bone. During later stages of tail regeneration, the distal CT mineralizes without endochondral ossification. The sub-perichondrium of the distal CT expresses Ihh, and the perichondrium directly calcifies without cartilage growth plate formation. The calcified CT perichondrium also contains a population of stem/progenitor cells that forms new cartilage in response to TGF-β stimulation. Treatment with the Ihh inhibitor cyclopamine inhibited both proximal CT ossification and distal CT calcification. Thus, while the two mineralization events are spatially, temporally, and mechanistically very different, they both involve Ihh. Taken together, these results suggest that Ihh regulates CT mineralization during two distinct stages of lizard tail regeneration.
    Developmental Biology 01/2015; DOI:10.1016/j.ydbio.2014.12.036 · 3.64 Impact Factor
  • Clinical Reviews in Bone and Mineral Metabolism 09/2014; 12(3):190-196. DOI:10.1007/s12018-014-9169-2


1 Download
Available from