Dana Gaddy

• PhD
• Professor at Texas A&M University

Estimation of body segment inertial properties (BSIPs) is a crucial step in development of inverse dynamics models. The goal of this study was to develop predictive models to estimate the mass, center of mass, and inertia tensor of the hindlimbs of sheep using easily obtainable morphometric data. In addition, this study presents a more comprehensiv...

Previous ovine motion capture studies have quantified front and rear limb kinematic and kinetic gait parameters; however the full-body biomechanics of sheep have yet to be fully quantified. In this work, an experimental design including the setup of a Vicon motion capture system, AMTI force platforms, a custom walkway with integrated force platform...

Background Tissue non-specific alkaline phosphatase (TNSALP; encoded by the ALPL gene) has a critical role in the postnatal regulation of phosphate homeostasis, yet how TNSALP activity and expression are regulated during pregnancy remain largely unknown. This study tested the hypothesis that progesterone (P4) and/or interferon tau (IFNT) regulate T...

Disclosure: J.C. Bertels: None. M. McCord: None. L.G. White: None. S. Huggins: None. D. Landrock: None. E.D. Giles: None. L.J. Suva: None. D. Gaddy: None. Hypophosphatasia (HPP) is a rare genetic disorder characterized by low enzymatic activity of tissue nonspecific alkaline phosphatase (TNSALP), resulting in decreased bone mineralization, muscle w...

Tissue-nonspecific alkaline phosphatase (TNSALP; encoded by ALPL gene) has a critical role in the regulation of phosphate homeostasis postnatally. However, the utero-placental expression of TNSALP and the role in phosphate transport in pregnancy is poorly understood. Estrous cycles of ewes were synchronized, and ewes were euthanized and hysterectom...

Humans and mice have the ability to regenerate the distal digit tip, the terminal phalanx (P3) in response to amputation. What distinguishes P3 regeneration from regenerative failure is formation of the blastema, a proliferative structure that undergoes morphogenesis to regenerate the amputated tissues. P3 regeneration is characterized by the phase...

C-type natriuretic peptide (CNP) activation of guanylyl cyclase-B (GC-B) catalyzes the synthesis of cGMP in chondrocytes and osteoblasts. Elevated cGMP stimulates long bone growth, and inactivating mutations in CNP or GC-B reduce cGMP, which causes dwarfism. GC-B7E/7E mice that express a GC-B mutant that cannot be inactivated by dephosphorylation e...

Hypophosphatasia (HPP) is the inherited error‐of‐metabolism caused by mutations in ALPL, reducing the function of tissue‐nonspecific alkaline phosphatase (TNAP/TNALP/TNSALP). HPP is characterized by defective skeletal and dental mineralization and is categorized into several clinical subtypes based on age of onset and severity of manifestations, th...

Individuals with Down syndrome (DS), the result of trisomy of human chromosome Hsa21 (Ts21), present with an array of skeletal abnormalities typified by altered craniofacial features, short stature and low bone mineral density (BMD). While bone deficits progress with age in both sexes, low bone mass is more pronounced in DS men than women and osteo...

It is long-established that innervation-dependent production of neurotrophic factors is required for blastema formation and epimorphic regeneration of appendages in fish and amphibians. The regenerating mouse digit tip and the human fingertip are mammalian models for epimorphic regeneration, and limb denervation in mice inhibits this response. A co...

This study aimed to determine whether the acceleration of conceptus development induced by administration of exogenous progesterone (P4) during the pre-implantation period of pregnancy alters calcium, phosphate, and vitamin D signaling at the maternal-conceptus interface. Suffolk ewes (n = 48) were mated to fertile rams and received daily intramusc...

Background Structural regeneration of amputated appendages by blastema-mediated, epimorphic regeneration is a process whose mechanisms are beginning to be employed for inducing regeneration. While epimorphic regeneration is classically studied in non-amniote vertebrates such as salamanders, mammals also possess a limited ability for epimorphic rege...

Given recent reports of expression of postnatal mineral transport regulators at the maternal-conceptus interface during the peri-implantation period, this study tested the hypothesis that progesterone (P4) and/or interferon tau (IFNT) regulate phosphate, calcium, and vitamin D signaling in the ovine endometrium. Mature Rambouillet ewes (n = 24) wer...

Simple Summary In the first two years following spinal cord injury, people lose up to 50% of bone below the injury. This injury-induced bone loss significantly affects rehabilitation and leaves people vulnerable to fractures and post-fracture complications, including lung and urinary tract infections, blood clots in the veins, and depression. Unfor...

Amputation injuries in mammals are typically non-regenerative, however joint regeneration is stimulated by BMP9 treatment (Yu et al., 2019) indicating the presence of latent articular chondrocyte progenitor cells. BMP9 induces a battery of chondrogenic genes in vivo, and a similar response is observed in cultures of amputation wound cells. Extended...

Normal calcium and bone homeostasis in the adult is virtually fully explained by the interactions of several key regulatory hormones, including parathyroid hormone, 1,25 dihydroxy vitamin D3, fibroblast growth factor-23, calcitonin, and sex steroids (estradiol and testosterone). In utero, bone and mineral metabolism is regulated differently from th...

Amputation of the mouse digit tip results in blastema‐mediated regeneration. In this model, new bone regenerates de novo to lengthen the amputated stump bone resulting in a functional replacement of the terminal phalangeal element along with associated non‐skeletal tissues. Physiological examples of bone repair, such as distraction osteogenesis and...

Mineralization of the fetal mammalian skeleton requires a hypercalcemic gradient across the placenta from mother to fetus. However, the mechanisms responsible for maintaining the placental transport of calcium remain poorly understood. This study aimed to identify calcium and vitamin D regulatory pathway components in ovine endometria and placentae...

Appropriate mineralization of the fetal skeleton requires an excess of phosphate in the fetus compared to the mother. However, mechanisms for placental phosphate transport are poorly understood. This study aimed to identify phosphate regulatory pathways in ovine endometria and placentae throughout gestation. Suffolk ewes were bred with fertile rams...

Bisphosphonates (BPs) are characterized by their ability to bind strongly to bone mineral and inhibit bone resorption. However, BPs exert a wide range of pharmacological activities beyond the inhibition of bone resorption, including the inhibition of cancer cell metastases and angiogenesis and the inhibition of proliferation and apoptosis in vitro....

ALPL encodes tissue-nonspecific alkaline phosphatase (TNAP), an enzyme expressed in bone, teeth, liver, and kidney. ALPL loss-of-function mutations cause hypophosphatasia (HPP), an inborn error-of-metabolism that produces skeletal and dental mineralization defects. Case reports describe widely varying dental phenotypes, making it unclear how HPP co...

Osteoarticular disease is a frequent complication of human brucellosis. Vaccination remains a critical component of brucellosis control but there are currently no vaccines for use in humans and no in vitro models for assessing safety of candidate vaccines in reference to development of bone lesions currently exist. While the effect of Brucella infe...

C-type natriuretic peptide (CNP) activation of guanylyl cyclase (GC)-B, also known as NPR2, stimulates cGMP synthesis and bone elongation. CNP activation requires the phosphorylation of multiple GC-B residues and dephosphorylation inactivates the receptor. GC-B7E/7E knockin mice, expressing a glutamate-substituted, “pseudophosphorylated,” form of G...

The utility of genetic engineering has increased significantly in recent years, particularly with the wide acceptance of CRISPR-Cas9 genome editing technology. The wide application of genome editing techniques provides a unique opportunity for musculoskeletal investigators to consider the examination of rare (and other) disease phenotypes as well a...

The availability of tools to accurately replicate the clinical phenotype of rare human diseases is a key step toward improved understanding of disease progression and the development of more effective therapeutics. We successfully generated the first large animal model of a rare human bone disease, hypophosphatasia (HPP) using CRISPR/Cas9 to introd...

Background Clodronate is prescribed to performance horses with lameness. Despite its clinical popularity, little research has been done to understand the effects of clodronate in the horse. Objectives Our objective was to determine if a single treatment with clodronate at the clinically approved dose altered bone remodelling, bone cell recruitment...

Hypophosphatasia (HPP) is a rare inherited disorder that affects the development of bones and teeth. The disease is caused by mutations in the tissue‐nonspecific alkaline phosphatase (TNSALP) gene ( ALPL ) and accompanied by a highly variable clinical presentation. Although HPP patient studies have advanced our understanding of HPP, as well as docu...

The Leprecan protein family which includes the prolyl 3-hydroxylase enzymes (P3H1, P3H2, and P3H3), the closely related cartilage-associated protein (CRTAP), and SC65 (Synaptonemal complex 65, aka P3H4, LEPREL4), is involved in the post-translational modification of fibrillar collagens. Mutations in CRTAP, P3H1 and P3H2 cause human genetic diseases...

Down syndrome (DS), characterized by trisomy of human chromosome 21, is associated with a variety of endocrine disorders as well as profound skeletal abnormalities. The low bone mass phenotype in DS is defined by low bone turnover due to decreased osteoclast and osteoblast activity, decreasing the utility of anti-resorptive agents in people with DS...

Bone is a common site for metastasis in breast cancer patients and is associated with a series of complications which significantly compromise patient survival, partially due to the advanced stage of disease at the time of detection. Currently, no clinically-approved biomarkers can identify or predict the development of bone metastasis. We recently...

Hypophosphatasia is a rare inherited disorder that affects the development of bones and teeth caused by mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Similar to other human disease models, the current models of HPP have been engineered exclusively in rodents – specifically mice harboring loss-of-function missense mutations...

Hypophosphatasia is a rare inherited disorder that affects the development of bones and teeth caused by mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Similar to other human disease models, the current models of HPP have been engineered exclusively in rodents – specifically mice harboring loss-of-function missense mutations...

We used a murine model of acute, post-traumatic osteomyelitis to evaluate the virulence of two divergent Staphylococcus aureus clinical isolates (the USA300 strain LAC and USA200 strain UAMS-1) and their isogenic sarA mutants. The results confirmed that both strains caused a comparable degree of the osteolysis and reactive new bone formation in the...

Obesity impairs reproductive functions through multiple mechanisms, possibly through disruption of ovarian function. We hypothesized that increased adiposity will lead to a pro-inflammatory gene signature and up-regulation of Egr-1 protein in ovaries from obese (OB, n=7) compared to lean (LN, n=10) female Sprague Dawley rats during the peri-implant...

This study examines acute and degenerative tissue responses to space-like radiation doses in a rodent model of simulated microgravity. We have studied four groups of rats, control (CON), irradiated (IR), irradiated and hindlimb suspended (IR-HLS), and suspended (HLS) that were maintained for two weeks. IR and IR+HLS groups were exposed to five sess...

In the context of breast cancer, the importance of the skeleton in the regulation of primary tumour development and as a site for subsequent metastasis is well characterized. Our understanding of the contributions made by the host bone and bone marrow cells increasingly demonstrates the extent of the interaction between tumour cells and normal host...

The process of osteoclastic bone resorption is complex and regulated at multiple levels. The role of osteoclast (OCL) fusion and motility in bone resorption are unclear, with the movement of OCL on bone largely unexplored. RANKL is a potent stimulator of murine osteoclastogenesis, and Activin A (ActA) enhances that stimulation in whole bone marrow....

This study examines acute and degenerative tissue responses to space‐like radiation doses in a rodent model of simulated microgravity. Three groups of rats, control (CON), irradiated (IR) and irradiated plus suspended (IR+HLS) were maintained for two weeks. IR and IR+HLS groups were exposed to radiation dose of 10GY. Body weights, soleus muscle wei...

Members of the Leprecan family of proteins include enzymes, prolyl 3-hydroxylase 1 (P3h1), P3h2 and P3h3, and non-enzymatic proteins, Crtap and Sc65. Mutations in CRTAP and LEPRE1 (encoding P3H1) have been associated with human disease such as recessive osteogenesis imperfecta, however, the function of Sc65 which is closely related and highly homol...

Background: Breast cancer bone metastasis is a complication that significantly compromises patient survival due, in part, to the lack of disease-specific biomarkers that allow early and accurate diagnosis. Methods: Using mass spectrometry protein profiling, plasma samples were screened from three independent breast cancer patient cohorts with and w...

Increased incidence of osteoporosis in Down syndrome has been reported, but etiology is not established. We report low bone turnover markers and bone mineral density (BMD) in a cohort of people with Down syndrome without consistent clinical risk factors. Our results should guide future studies and treatments for this common problem. Introduction To...

Trisomy 21 affects virtually every organ system and results in the complex clinical presentation of Down syndrome (DS). Patterns of differences are now being recognized as patients' age and these patterns bring about new opportunities for disease prevention and treatment. Low bone mineral density (BMD) has been reported in many studies of males and...

Age-related bone phenotype in Ts65Dn mice. (A) Micro CT reconstructions of proximal tibia and femur from 3-month (left column) and 24-month (right column) old WT (top) and Ts65Dn (bottom) mice. Low bone volume and cortical thinning is evident. (B). Paraffin-embedded decalcified histological sections of proximal tibia from 3-month (left column) and...

Decreased cortical bone parameters of 24-month old Ts65Dn mice. Determination of femoral midshaft cortical parameters from Micro CT reconstructions of mid shaft femur shows significant decreases compared to WT in (A) cortical cross sectional area, (B) total cross sectional area, (C) periosteal perimeter, (D) Peak load (load tolerated at the breakin...

The aim of this study is to compare the effects of simulated microgravity in tail suspended (TS) as well as in pelvic suspended (PS) rats mimicking aspects of prolonged bed rest and sub‐clinical insulinopenia. Materials and Methods Adult male Sprague‐Dawley rats divided into suspended and control‐non‐suspended groups (6 each per group), were subje...

Given the aging population and the increased incidence of fracture in the elderly population, the need exists for agents that can enhance bone healing, particularly in situations of delayed fracture healing and/or non-union. Our previous studies demonstrated that overexpression of the gonadal peptide, human inhibin A (hInhA), in transgenic mice enh...

Spaceflight and simulated microgravity often associate with pain and prediabetes. Streptozotocin (STZ)-induced moderate insulinopenia rat models of prediabetes result in pressure hyperalgesia. The current study was designed to determine whether or not simulated microgravity induced by hind limb suspension (HLS) in rats lead to insulinopenia and pre...

Localized irradiation is a common treatment modality for malignancies in the pelvic-abdominal cavity. We report here on the changes in bone mass and strength in mice 7-14 days after abdominal irradiation. Male C57BL/6 mice of 10-12 weeks of age were given a single-dose (0, 5, 10, 15 or 20 Gy) or fractionated (3 Gy × 2 per day × 7.5 days) X rays to...

The pancreas plays an important role in regulating many of the key endocrine hormones and digestive enzymes that are required for nutrition and survival of the organism. This study examines the pancreatic histology and associated biochemical changes in rats on hind limb suspension (HLS) after exposure to simulated microgravity. Results show that MD...

Leptin, the product of the Lep gene, reports levels of adiposity to the hypothalamus and other regulatory cells, including pituitary somatotropes, which secrete GH. Leptin deficiency is associated with a decline in somatotrope numbers and function, suggesting that leptin may be important in their maintenance. This hypothesis was tested in a new ani...

Leptin, the product of the Lep gene, reports levels of adiposity to the hypothalamus and other regulatory cells, including pituitary somatotropes, which secrete GH. Leptin deficiency is associated with a decline in somatotrope numbers and function, suggesting that leptin may be important in their maintenance. This hypothesis was tested in a new ani...

Leptin, the product of the Lep gene, reports levels of adiposity to the hypothalamus and other regulatory cells, including pituitary somatotropes, which secrete GH. Leptin deficiency is associated with a decline in somatotrope numbers and function, suggesting that leptin may be important in their maintenance. This hypothesis was tested in a new ani...

Although injury is a major cause of death and disability, concepts of injury prevention have not been present in the curricula of most medical schools. There have been recent calls in the literature, including a 2005 report from the Association of American Medical Colleges, for the addition of injury prevention concepts into medical school educatio...

Krüppel-like factors (KLFs) are zinc finger-containing transcription factors that are implicated in diverse physiological processes in the reproductive tract. We previously showed that KLF9, a 33kDa protein family member, influenced estrogen receptor-α (ERα) expression and activity in mouse and human uterine cells, suggesting its potential role as...

Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates secretion of pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which directly regulate ovarian function. Pituitary FSH can modulate osteoclast development, and thereby influence bone turnover. Pituitary oxytocin and prolactin effects on the skeleton are not merel...

Accumulating evidence demonstrates increasing bone turnover and bone loss in women prior to menopause and decreases in serum estradiol levels. Increased follicle-stimulating hormone levels have been correlated with some of these peri-menopausal changes. However, decreases in gonadal inhibins of the transforming growth factor (TGF)-beta superfamily...

Inappropriate early exposure of the hormone-responsive uterus to estrogenic compounds is associated with increased risk for adult reproductive diseases including endometrial cancers. While the dysregulation of estrogen receptor-alpha (ESR1) signaling is well acknowledged to mediate early events in tumor initiation, mechanisms contributing to sustai...

There is both cellular and physiological evidence demonstrating that both Activins and Inhibins regulate osteoblastogenesis and osteoclastogenesis, and regulate bone mass in vivo. Although Activins and Inhibins were initially isolated from the gonad, Activins are also produced and stored in bone, whereas Inhibins exert their regulation on bone cell...

Dipeptidyl peptidase (DPP) IV activity and/or structure homologues (DASH) are serine proteases implicated in tumourigenesis. We previously found that a DASH protease, fibroblast activation protein (FAP), was involved in osteoclast-induced myeloma growth. Here we further demonstrated expression of various adhesion molecules in osteoclasts cultured a...

Leptin restores growth hormone (GH) in leptin-deficient animals, suggesting a role in somatotrope maintenance. To determine leptin’s importance to somatotropes, we ablated the leptin receptor (LEPR) selectively using targeted Cre-recombinase in somatotropes of mice bearing two floxed alleles of lepr exon 17, thereby removing the JAK binding site of...

Leptin restores growth hormone (GH) in leptin‐deficient animals, suggesting a role in somatotrope maintenance. To determine leptin's importance to somatotropes, we ablated the leptin receptor (LEPR) selectively using targeted Cre‐recombinase in somatotropes of mice bearing two floxed alleles of LEPR exon 17, thereby removing the JAK binding site of...

Inhibins A and B are gonadal peptide members of the transforming growth factor-beta superfamily that serve as negative feedback regulators of pituitary follicle-stimulating hormone (FSH). Accumulating evidence suggests that bone turnover and bone loss increase in women before menopause and the decrease in serum estradiol levels. Increased FSH level...

Fibroblast activation protein (FAP), a cell surface serine protease with both dipeptidyl peptidase and collagenase activity, is selectively expressed by tumor stroma and involved in tumor metastasis. We have reported that FAP is upregulated in myelomatous bone and is overexpressed in osteoclasts after coculture with myeloma (MM) cells. FAP is not e...

Gonadal function plays a major role in bone homeostasis. It is widely held that the skeletal consequences of hypogonadism are solely due to a loss of sex steroids; however, increases in bone turnover begin during perimenopause before decreases in serum estradiol levels. These data and our demonstration that inhibins acutely regulate bone cell diffe...

Disuse has been shown to cause a rapid and dramatic loss of skeletal mass and strength in the load-bearing bones of young and mature animals and humans. However, little is known about the skeletal effects of disuse in aged mammals. The present study was designed to determine whether the skeletal effects of disuse are maintained with extreme age. Fi...

Skeletal muscle atrophy is associated with an increase in apoptosis, and we showed previously that endonuclease G (EndoG) is localized to nuclei following unloading. The goal of this study was to determine whether the onset of apoptosis in response to disuse was consistent with the hypothesis that EndoG is involved in myofiber nuclear loss. Atrophy...

Although the control of bone metastasis has been the focus of intensive investigation, relatively little is known about the molecular mechanisms that regulate or predict the process, even though widespread skeletal dissemination is an important step in the progression of many tumors. As a result, understanding the complex interactions contributing...

Flywheel-based resistance exercise (RE) attenuates muscle atrophy during hindlimb suspension. We have previously shown that protein synthesis is elevated in response to RE, but the effect on protein degradation, cell proliferation, or apoptosis was not investigated. We hypothesized that, in addition to affecting protein synthesis, RE inhibits proce...

The central position of estrogen in the physiological and pharmacological control of bone resorption is now challenged by evidence from mouse genetics of estrogen-independent control by pituitary FSH.

Recent studies have implicated the mTOR-signaling pathway as a primary component for muscle growth in mammals. The purpose of this investigation was to examine signaling pathways for muscle protein synthesis after resistance exercise. Sprague-Dawley rats (male, 6 mo old) were assigned to either resistance exercise or control groups. Resistance exer...

Longitudinal clinical studies demonstrate that increases in bone turnover that occur in perimenopausal women correlate better with elevated serum FSH than with changes in serum estradiol (E2). This perimenopausal rise in FSH is due to a selective decrease in ovarian inhibin B (InhB). Our previous demonstration that inhibins suppress both osteoblast...

Multiple myeloma (MM) growth in the bone marrow is associated with increased osteoclast activity and a reduced number of osteoblasts. Experimental studies suggest that bone disease drives the progression of MM. Whereas those studies focused on the critical role of myeloma-induced osteoclastogenesis in disease progression, little is known about the...

Bone is a common site of cancer metastasis. Breast, prostate, and lung cancers show a predilection to metastasize to bone. Recently, we reported that the chemokine interleukin 8 (IL-8) stimulates both human osteoclast formation and bone resorption. IL-8 mRNA expression was surveyed in a panel of human breast cancer lines MDA-MET, MDA-MB-231, MDA-MB...

For decades, the processes that couple bone architecture and mass to function have been investigated and characterized. It is well known, and now well accepted, that increases in exercise and loading of bone are associated with increased bone mass, and that disuse induces osteopenia. However, the mechanisms by which disuse leads to bone loss remain...

Therapeutic radiation delivered to bone and the adjacent local tissues before allograft limb-salvage surgery has been associated with poor graft incorporation and higher numbers of clinical complications. Our objective was to determine the effect of preoperative radiation therapy on specific histologic, molecular and structural parameters of large-...