We have created an allelic PTHrP-lacZ knockin mouse that provides a simple and sensitive reporter of PTHrP gene expression. The PTHrP-lacZ mouse demonstrates PTHrP gene expression in a wide variety of locations, including several that were previously unappreciated or underappreciated. These include: 1) the insertion sites of tendons and ligaments into cortical bone (collectively referred to as entheses), 2) the periosteum itself, particularly during bone growth, and 3) superficial layers of articular cartilage. In all of these sites, the PTHrP gene seems to be mechanically-induced. We have not identified PTHrP/lacZ expression in any internal bone cell population. We propose that PTHrP functions """"""""at the gates"""""""" of endochondral bones, namely, at the interface of skeletal elements with each other and with surrounding muscles and connective tissues.
Aim 1. We will characterize PTHrP, PPR, and cell marker expression in selected periosteal sites and entheses in order to: a) identify the cells that participate in paracrine signaling in these sites and b) enable the functional experiments proposed in Aims 2 and 3. We have also bred a single lacZ allele-containing PTHrP-null mouse that serves as a reporter system for Indian hedgehog regulation of PTHrP gene expression.
Aim 2 comprises two overlapping subaims. One involves mechanical regulation of PTHrP expression and chondrocyte or bone cell function(s) in the periosteum, fibrocartilage, and fibrous entheses. The second considers specific candidate PTHrP functions in the periosteum, including a) mediation of force-driven periosteal bone formation, b) regulation of the modeling of the metaphysis and diaphysis during linear growth, and c) potential PTHrP involvement in the sexual dimorphism of periosteal bone.
Aim 3. We will employ the scleraxis and/or periostin genes in order to create mouse models in which PTHrP is conditionally deleted in the periosteum and entheses.

Public Health Relevance

. Most bones develop from an initial cartilagenous mold. Such bones are comprised of two separate compartments: internal (or endosteal) bone and external (or periosteal) bone. Endosteal bone evolved principally to subserve reproductive demands and is primarily regulated by estrogen. Periosteal bone accounts for the larger and stronger skeleton in the male and is regulated primarily by androgens and mechanical forces (and inhibited by estrogen). We have identified parathyroid hormone-related protein (PTHrP) in the periosteum and ligament and tendon insertions into periosteal bone and also in articular cartilage the joints. In all of these sites, PTHrP production is regulated by mechanical force. We propose that PTHrP regulates cartilage and bone cell functions """"""""at the gates"""""""" on long bones, namely, at the interface of the bones with each other and with surrounding muscles and connective tissues. Examples of such functions include PTHrP mediation of the shaping of bones by mechanical force, the sculpting of bones as they grow, and the sex steroid modulation of skeletal size.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062515-29
Application #
7804480
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Malozowski, Saul N
Project Start
1981-07-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
29
Fiscal Year
2010
Total Cost
$503,802
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Wang, Meina; Nasiri, Ali R; Broadus, Arthur E et al. (2015) Periosteal PTHrP Regulates Cortical Bone Remodeling During Fracture Healing. Bone 81:104-11
Wang, Meina; Nasiri, Ali; VanHouten, Joshua N et al. (2014) The remarkable migration of the medial collateral ligament. J Anat 224:490-8
Wang, Meina; VanHouten, Joshua N; Nasiri, Ali R et al. (2014) Periosteal PTHrP regulates cortical bone modeling during linear growth in mice. J Anat 225:71-82
Wang, Meina; VanHouten, Joshua N; Nasiri, Ali R et al. (2013) PTHrP regulates the modeling of cortical bone surfaces at fibrous insertion sites during growth. J Bone Miner Res 28:598-607
Karaplis, Andrew C; Bai, Xiuying; Falet, Jean-Pierre et al. (2012) Mineralizing enthesopathy is a common feature of renal phosphate-wasting disorders attributed to FGF23 and is exacerbated by standard therapy in hyp mice. Endocrinology 153:5906-17
Macica, Carolyn; Liang, Guoying; Nasiri, Ali et al. (2011) Genetic evidence of the regulatory role of parathyroid hormone-related protein in articular chondrocyte maintenance in an experimental mouse model. Arthritis Rheum 63:3333-43
Liang, Guoying; Katz, Lee D; Insogna, Karl L et al. (2009) Survey of the enthesopathy of X-linked hypophosphatemia and its characterization in Hyp mice. Calcif Tissue Int 85:235-46
Chen, Xuesong; Macica, Carolyn M; Nasiri, Ali et al. (2008) Regulation of articular chondrocyte proliferation and differentiation by indian hedgehog and parathyroid hormone-related protein in mice. Arthritis Rheum 58:3788-97
Chen, Xuesong; Macica, Carolyn; Nasiri, Ali et al. (2007) Mechanical regulation of PTHrP expression in entheses. Bone 41:752-9
Liang, Guoying; Cline, Gary W; Macica, Carolyn M (2007) IGF-1 stimulates de novo fatty acid biosynthesis by Schwann cells during myelination. Glia 55:632-41

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