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Abstract 2005 MHE Conference
Henry M. Kronenberg M.D.,PH.D.
Endocrine Unit, Massachusetts General Hospital and
Harvard Medical School, Boston, MA 02114
Chondrocytes in the growth plate are the engine that causes bone lengthening. Chondrocytes
proliferate and secrete matrix. They then stop proliferating, enlarge several fold (hypertrophy),
mineralize the matrix surrounding them, and then die. The matrix remaining provides a scaffold for
subsequent formation of bone by osteoblasts.
To assure a proper balance between chondrocyte proliferation and hypertrophy, elaborate regulatory
mechanisms have evolved. Parathyroid hormone-related protein (PTHrP), a relative of the
calcium-regulating hormone, parathyroid hormone, is secreted by perichondrial cells and
chondrocytes at the ends of long bones of the limb.
PTHrP acts to keep chondrocytes proliferating, thereby allowing the generation of more chondrocytes
and delaying the onset of chondrocyte hypertrophy. Only when chondrocytes bearing receptors for
PTHrP are sufficiently far from a source of PTHrP do the chondrocytes then stop proliferating.
PTHrP works by activating a receptor of the G protein-coupled receptor family. Activation stimulates
the heterotrimeric G protein, Gs; this activation leads to generation of cyclic AMP and activation of
protein kinase A. These processes lead to suppression of the cell cycle inhibitor, p57, and also
suppression of the expression of the transcription factor, Runx2. Suppression of p57 is a major
mechanism that results in the continued proliferation of chondrocytes. Since Runx2 is a major
inducer of chondrocyte hypertrophy, the suppression of Runx2 expression by PTHrP also
contributes to the continued proliferation and delay of hypertrophy of chondrocytes.
As chondrocytes stop proliferating, they begin secreting Indian hedgehog. Indian hedgehog (Ihh)
has multiple roles in regulating the growth plate. Ihh stimulates the synthesis of PTHrP, a role that
then leads to further expansion of the layers of proliferating chondrocytes.
Since these proliferating chondrocytes do not synthesize Ihh, the stimulation of PTHrP synthesis by
Ihh serves to negatively regulate the expression of Ihh. Ihh also accelerates the conversion of
round chondrocytes, found at the top of the growth plate, into flat columnar chondrocytes. Since
the flat columns formed by these cells align in the primary axis of growth of the growth plate, this
action of Ihh serves to help determine the final length and shape of the bones. Ihh also stimulates
the proliferation of chondrocytes and acts on adjacent perichondrial cells to convert them to
osteoblasts. Thus, Ihh is a master regulator of the growth plate which controls chondrocyte
proliferation and differentiation, as well as the differentiation of adjacent osteoblasts.
Henry M. Kronenberg M.D.,PH.D.
Endocrine Unit, Massachusetts General Hospital and
Harvard Medical School, Boston, MA 02114
Chondrocytes in the growth plate are the engine that causes bone lengthening. Chondrocytes
proliferate and secrete matrix. They then stop proliferating, enlarge several fold (hypertrophy),
mineralize the matrix surrounding them, and then die. The matrix remaining provides a scaffold for
subsequent formation of bone by osteoblasts.
To assure a proper balance between chondrocyte proliferation and hypertrophy, elaborate regulatory
mechanisms have evolved. Parathyroid hormone-related protein (PTHrP), a relative of the
calcium-regulating hormone, parathyroid hormone, is secreted by perichondrial cells and
chondrocytes at the ends of long bones of the limb.
PTHrP acts to keep chondrocytes proliferating, thereby allowing the generation of more chondrocytes
and delaying the onset of chondrocyte hypertrophy. Only when chondrocytes bearing receptors for
PTHrP are sufficiently far from a source of PTHrP do the chondrocytes then stop proliferating.
PTHrP works by activating a receptor of the G protein-coupled receptor family. Activation stimulates
the heterotrimeric G protein, Gs; this activation leads to generation of cyclic AMP and activation of
protein kinase A. These processes lead to suppression of the cell cycle inhibitor, p57, and also
suppression of the expression of the transcription factor, Runx2. Suppression of p57 is a major
mechanism that results in the continued proliferation of chondrocytes. Since Runx2 is a major
inducer of chondrocyte hypertrophy, the suppression of Runx2 expression by PTHrP also
contributes to the continued proliferation and delay of hypertrophy of chondrocytes.
As chondrocytes stop proliferating, they begin secreting Indian hedgehog. Indian hedgehog (Ihh)
has multiple roles in regulating the growth plate. Ihh stimulates the synthesis of PTHrP, a role that
then leads to further expansion of the layers of proliferating chondrocytes.
Since these proliferating chondrocytes do not synthesize Ihh, the stimulation of PTHrP synthesis by
Ihh serves to negatively regulate the expression of Ihh. Ihh also accelerates the conversion of
round chondrocytes, found at the top of the growth plate, into flat columnar chondrocytes. Since
the flat columns formed by these cells align in the primary axis of growth of the growth plate, this
action of Ihh serves to help determine the final length and shape of the bones. Ihh also stimulates
the proliferation of chondrocytes and acts on adjacent perichondrial cells to convert them to
osteoblasts. Thus, Ihh is a master regulator of the growth plate which controls chondrocyte
proliferation and differentiation, as well as the differentiation of adjacent osteoblasts.
Henry Kronenberg, research focuses on the regulation of bone and mineral metabolism and bone
development. Particular emphasis is placed on parathyroid hormone, parathyroid hormone-related
protein, and vitamin D. The work includes both clinical investigation, as exemplified by the Specialized
Center for Research in Osteoporosis, funded by NIH, which is conducting a trial of parathyroid
hormone therapy for osteoporosis, and fundamental molecular research, such as studies of the
mechanisms of action of the PTH/PTHrP receptor. Bone development is studied through the creation
of a series of gene "knockout" mice.
Dr. Kronenberg serves on the Scientific and Medical Advisory Board of the MHE Research
Foundation and was past president 1993-1994 of the The American Society for Bone and
Mineral Research (ASBMR)
development. Particular emphasis is placed on parathyroid hormone, parathyroid hormone-related
protein, and vitamin D. The work includes both clinical investigation, as exemplified by the Specialized
Center for Research in Osteoporosis, funded by NIH, which is conducting a trial of parathyroid
hormone therapy for osteoporosis, and fundamental molecular research, such as studies of the
mechanisms of action of the PTH/PTHrP receptor. Bone development is studied through the creation
of a series of gene "knockout" mice.
Dr. Kronenberg serves on the Scientific and Medical Advisory Board of the MHE Research
Foundation and was past president 1993-1994 of the The American Society for Bone and
Mineral Research (ASBMR)
Research authored by Dr. Kronenberg
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List of Publications via PubMed
(NIH National Library of Medicine)
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List of Publications via PubMed
(NIH National Library of Medicine)
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| Dr. Kronenberg's research |
How PTHrP regulates chondrocytes in the growth plate
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Video presentation link of Dr. Kronenberg's presentaton during the ASBMR conference held
on September 2006
The MHE Research would like to thank ASBMR for the use of the presentation on the MHE
Research Foundation website.
To view this video presentation given by Dr. Henry Kronenberg during this conference please click
the link tab
on September 2006
The MHE Research would like to thank ASBMR for the use of the presentation on the MHE
Research Foundation website.
To view this video presentation given by Dr. Henry Kronenberg during this conference please click
the link tab
For more detailed information concerning the Perichondrium, chondrocytes, PTHrP, Ihh
and other signaling pathways affected in by the defect in the EXT genes please view the
video.
April 25–28, 2007, the 2nd Conference on Skeletal Biology and Medicine held in NYC.
This meeting, was jointly hosted at the New York Academy of Sciences and Mount Sinai
School of Medicine, was organized and chaired by Mone Zaidi, professor of endocrinology,
geriatrics and adult development, and structural and chemical biology at Mount Sinai. Cochairs were
Gerard Karsenty of Columbia University and Steven Teitelbaum of the Washington University School
of Medicine.
The MHE Research would like to thank all for the use of the presentation on the MHE
Research Foundation website.
To view this video presentation given by Dr. Henry Kronenberg during this conference please click
the link tab
and other signaling pathways affected in by the defect in the EXT genes please view the
video.
April 25–28, 2007, the 2nd Conference on Skeletal Biology and Medicine held in NYC.
This meeting, was jointly hosted at the New York Academy of Sciences and Mount Sinai
School of Medicine, was organized and chaired by Mone Zaidi, professor of endocrinology,
geriatrics and adult development, and structural and chemical biology at Mount Sinai. Cochairs were
Gerard Karsenty of Columbia University and Steven Teitelbaum of the Washington University School
of Medicine.
The MHE Research would like to thank all for the use of the presentation on the MHE
Research Foundation website.
To view this video presentation given by Dr. Henry Kronenberg during this conference please click
the link tab
Questions to the Scientific & Medical Advisory Board,
Please use the contact Scientific & Medical Advisory Board Tab or you may email directly
AdvisoryBoard@mheresearchfoundation.org
Please use the contact Scientific & Medical Advisory Board Tab or you may email directly
AdvisoryBoard@mheresearchfoundation.org
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Have a Question or Comments for the Board of Directors,
Please use the contact Board of Directors Tab or General enquiries can be emailed to
Boardofdirectors@mheresearchfoundation.org
Please use the contact Board of Directors Tab or General enquiries can be emailed to
Boardofdirectors@mheresearchfoundation.org
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National Library of Medicine, Directory of Health Organizations (SIS) website, as well as the link for Patient
Information on The Diseases Database a cross-referenced index of human disease, and the Intute: health & life
sciences a free online service providing access to the very best Web resources for education and research
located in the UK
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