Date of Award

2018

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. Maria A Serrat, Committee Chairperson

Second Advisor

Dr. Richard Egleton

Third Advisor

Dr. John Kopchick

Fourth Advisor

Dr. Travis Salisbury

Fifth Advisor

Dr. Monica Valentovic

Abstract

Bone elongation disorders can lead to painful musculoskeletal disabilities in adulthood. Existing treatment options to correct left-right asymmetry in limb length include invasive surgeries and/or drug regimens. These are often only partially effective. Previous studies in weanling mice have shown that a daily application of mild heat (40°C) to limbs on one side of the body could be used to noninvasively enhance bone elongation. However, the impact of heat-treatment on bone at the cellular level remains elusive. The epiphyseal growth plate, the band of cartilage located at each end of long bones, is the main site of longitudinal growth and is regulated by local and systemic growth factors. Insulin-like growth factor 1 (IGF1) is the major regulator of growth and controls bone elongation by promoting chondrocyte proliferation and hypertrophy. The objective of this study was to build upon an established method of targeted limb heating to determine how heat-treatment influences IGF1 action in the growth plate. This study tests the hypothesis that exposure to warm temperature augments the actions of IGF1 in the growth plate and permanently increases length of the extremities. This dissertation demonstrates that differences of less than 1.5% are functionally significant measured by a nearly 20% increase in hindlimb weight bearing on heat-treated sides. Heat-enhanced bone elongation is documented in female C57BL/6 mice after 7 days of heat-treatment during the most active period of growth from 3-4 weeks of age. This increase in bone elongation is accompanied by increased chondrocyte proliferation and hypertrophy in the proximal tibial growth plate. Moreover, this study is the first to show that targeted limb-heating impacts local action of IGF1 in growth plate chondrocytes. Results suggest that heat-induced limb length is IGF1 dependent since the growth effects are attenuated when IGF1 activity is blocked. Administration of a low dose of IGF1 (2.5mg/kg) was found to augment heat enhanced bone elongation and effects were sustained to skeletal maturity (12 weeks of age). These studies help contribute to the ultimate goal of developing a noninvasive method for lengthening bones that may translate in a clinical setting to treat linear growth disorders in children.

Subject(s)

Musculoskeletal system -- Research.

Extremities (Anatomy) -- Research.

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