Fractures are a common injury in the United States and can lead to severe morbidity, high medical costs and significant mortality, especially in the elderly. Failures of healing, including cases of nonunion, secondary displacement and avascular necrosis, require repeated invasive surgery with decreased success rate with subsequent surgeries. The etiology underlying such bone repair failures is unknown but can be informed by a better understanding of the molecular mechanisms regulating endochondral ossification that includes mesenchymal condensation, chondrocyte differentiation and hypertrophy to form a cartilaginou anlagen that is then invaded by blood vessels, which brings osteoblasts and osteoclasts to form bone. Each step during endochondral ossification is tightly controlled by a number of growth hormones, cytokines and transcription factors. Work from our laboratory identified a transcription factor of the Creb family Atf4 that regulates chondrocyte proliferation, differentiation, and osteoblast maturation via activating the transcription of Indian hedgehog (Ihh), receptor activator of nuclear factor-?B ligand (Rankl) and osteocalcin (Ocn), respectively. Global Atf4 deficiency (Atf4-/-) led to dwarfism and severe osteopenia in mice. Surprisingly, restoration of Atf4 expression specifically in chondrocytes of the Atf4-/- mice not only completely rescued their size but also their bone mass defects. This finding strongly suggests that Atf4 in chondrocytes (chAtf4), but not it in osteoblasts (obAtf4), plays an indispensible role in the control of endochondral ossification and the chAtf4 is critical to the coupling between growth plate elongation and bone mass accrual after birth. What remains to be understood is how the chAtf4 versus the obAtf4, influences the set of hormones, growth factors, cytokines, and transcription factors involved in bone modeling and remodeling. Our central hypothesis is that chAtf4 is a critical transcriptional homeostat for the harmonious coupling between cartilage formation and bone modeling during development and bone repair. We propose the following specific aims to address this hypothesis using animal models.
Aim 1. To determine whether chAtf4 controls the conversion of cartilage to bone via its regulation of Mmp13 and Rankl transcription.
Aim 2. To elucidate whether obAtf4 is necessary for bone remodeling in adults.
Aim 3. To determine whether Atf4 is required in adults for proper transition between the phases of endochondral bone repair. Impact. Among the osteoblast differentiation factors Atf4 is unique for studies focusing on the regulators of cartilage to bone transition because its null mutants survive postnatally and it is expressed in all the subpopulation of chondrocytes. Thus the temporal and spatial function of Atf4 will provides us a unique opportunity to gain insights into mechanisms underlying the physiological processes during skeletal development and pathological conditions in fracture repair, nonunion, osteoarthritis.

Public Health Relevance

Failure of cartilage to bone transition during endochondral bone formation often leads to skeletal diseases such as dwarfism and nonunion in adults. Nonunion is a serious complication of fracture that causes persistent pain, impaired mobility, and loss of weight bearing ability. The proposed study will identify molecules controlling the transition of cartilage to bone, thereby informing our curative strategies for diseases in which these processes are affected.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
7R01AR067303-03
Application #
9538390
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chen, Faye H
Project Start
2017-09-01
Project End
2020-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhu, Jing; Li, Xiao; Qi, Hao et al. (2017) Oxidative and anti-oxidative status in muscle of young rats in response to six protein diets. Sci Rep 7:13184
Karolak, Matthew R; Yang, Xiangli; Elefteriou, Florent (2015) FGFR1 signaling in hypertrophic chondrocytes is attenuated by the Ras-GAP neurofibromin during endochondral bone formation. Hum Mol Genet 24:2552-64
Makowski, Alexander J; Uppuganti, Sasidhar; Wadeer, Sandra A et al. (2014) The loss of activating transcription factor 4 (ATF4) reduces bone toughness and fracture toughness. Bone 62:1-9
Campbell, J Preston; Karolak, Matthew R; Ma, Yun et al. (2012) Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice. PLoS Biol 10:e1001363