Maria A. Serrat, PhD
Phone: (304) 696-7392
Appalachia (WV) leads the nation in childhood obesity with about 1 in 3 children already overweight or obese. Obese children have higher rates of linear growth, accelerated skeletal maturation, and diminished bone quality. These factors can contribute to painful and debilitating conditions such as limb bowing, joint instability, fractures, and slipped capital femoral epiphyses. Insulin-like growth factor (IGF)-I, is one of two essential hormones (Growth Hormone is the other) needed for proper bone growth and is altered in obesity. Novel preliminary data demonstrate that IGF binding proteins (IGFBPs) may regulate bone elongation by entrapping IGF-I and limiting its transport into the growth plate; however, IGFBPs levels are diminished in obesity. Thus, the overall hypothesis is that a decrease in local IGF binding proteins promotes bone lengthening by allowing more IGF-I transport into growth plates. Better understanding of how the perichondrium IGF binding proteins regulate IGF-I transport into growth plates will potentially result in IGFBP based therapies to modulate the rate of bone elongation in obesity, and thus minimize the associated obesity related morbidities of childhood.
The Serrat Laboratory specializes in growth and morphology of the postnatal skeleton. We use in vivo models to investigate the physiological regulation of bone elongation and the impact of temperature on the bone lengthening process. One area of focus is on heat-enhanced molecular delivery to skeletal growth plates, the bands of cartilage at the ends of bones where lengthening occurs (Fig. 1).
Growth plate disorders have many different underlying causes ranging from injury and illness to genetic bone diseases. These conditions can lead to limb length inequality and a lifetime of serious orthopaedic problems such as scoliosis, chronic back pain, and osteoarthritis. Bone elongation disorders are challenging to treat because cartilage growth plates are not penetrated by blood vessels like typical vascularized organs (Fig. 1).
Targeting systemic drugs into cartilage is extremely difficult, and treatment options are often limited to painful corrective surgeries and/or expensive drug regimens. Noninvasive heat therapy could be a novel and cost-effective way to offset linear growth impediments, since our lab has previously demonstrated that warm temperature can increase bone length in experimental animals (Fig. 2).
Research in our lab takes an integrated, whole animal approach to these problems by employing tools such as multiphoton-based live animal imaging (Fig. 3). This technique allows us to evaluate heat-based therapies for augmenting delivery of systemic bone lengthening drugs across vascular-cartilage interfaces of the growing skeleton in vivo. Ongoing projects use real-time multiphoton microscopy and a unique limb-heating model to test the relationship between temperature, bone lengthening, and vascular access to growth plates. This research has practical relevance for treating a spectrum of linear growth disorder in children. Our goal is to develop noninvasive heat-based alternatives that can be applied to a wide range of growth-limiting conditions. Results could potentially lead to new treatment modalities with better outcomes by reducing amount, toxicity and costs of high-dose systemic pharmaceuticals.
Multiphoton microscopy is an emerging technology for live animal imaging that offers exciting possibilities for the study of growth plate dynamics in vivo. In collaboration with colleagues at Cornell University, we developed a unique platform for imaging intact skeletal growth plates that we use to assess how systemic regulators arrive at and move within the cartilage matrix of the growth plate under various experimental conditions. This system provides a new mechanism for understanding the physiological regulation of bone growth through the ability to dynamically measure changes in molecular transport to the growth plate of a living animal (Fig. 3). Using biologically-inert dextrans as size-proxies for systemic regulators, we have shown that heat can increase real-time entry of large molecules into growth plate cartilage in vivo (Serrat, Efaw, and Williams, 2014). We are now using fluorescently-labeled proteins to quantify heat-enhanced access of biologically-active molecules into growth plates of live, intact mice.
Environmental temperature impact on bone and cartilage growth.
Serrat MA. Compr Physiol. 2014 Apr;4(2):621-55. doi: 10.1002/cphy.c130023.
PMID: 24715562 [PubMed - in process]
Hindlimb heating increases vascular access of large molecules to murine tibial growth plates measured by in vivo multiphoton imaging.
Serrat MA, Efaw ML, Williams RM. J Appl Physiol (1985). 2014 Feb 15;116(4):425-38. doi: 10.1152/japplphysiol.01212.2013. Epub 2013 Dec 26. PMID: 24371019 [PubMed - in process]
Allen’s rule revisited: temperature influences bone elongation during a critical period of postnatal development.
Serrat MA. Anat Rec (Hoboken). 2013 Oct;296(10):1534-45. doi: 10.1002/ar.22763. Epub 2013 Aug 19. PMID: 23956063 [PubMed - indexed for MEDLINE]
Exercise mitigates the stunting effect of cold temperature on limb elongation in mice by increasing solute delivery to the growth plate.
Serrat MA, Williams RM, Farnum CE. J Appl Physiol (1985). 2010 Dec;109(6):1869-79. doi: 10.1152/japplphysiol.01022.2010. Epub 2010 Oct 7. PMID: 20930127 [PubMed - indexed for MEDLINE] Free PMC Article This paper used in vivo multiphoton microscopy to image growth plate cartilage with collaborators at Cornell University.
Serrat MA. Measuring bone blood supply in mice using fluorescent microspheres. Nature Protocols. 4(12): 1749-58. 2009. Single-author paper utilizing techniques developed by Dr. Serrat while she was a student at Kent State University.
Gabriela Ion, Ph.D. – Research Instructor
Holly Racine – Biomedical Sciences Ph.D. Candidate
Chad Meadows – Undergraduate Student