Louis C Gerstenfeld

Boston University | BU · Department of Orthopaedic Surgery

Prior studies of acute phosphate restriction during the endochondral phase of fracture healing showed delayed chondrocyte differentiation was mechanistically linked to decreased bone morphogenetic protein signaling. In the present study, transcriptomic analysis of fracture callus gene expression in three strains of mice was used to identify differe...

The expression of Prx1 has been used as a marker to define the skeletal stem cells (SSCs) populations found within the bone marrow and periosteum that contribute to bone regeneration. However, Prx1 expressing SSCs (Prx1-SSCs) are not restricted to the bone compartments, but are also located within the muscle and able to contribute to ectopic bone f...

Genome-wide association studies (GWASs) for bone mineral density (BMD) in humans have identified over 1100 associations to date. However, identifying causal genes implicated by such studies has been challenging. Recent advances in the development of transcriptome reference datasets and computational approaches such as transcriptome-wide association...

Past studies described interactions between normal megakaryocytes, the platelet precursors, and bone cell precursors in the bone marrow. This relationship has also been studied in context of various mutations associated with increased number of megakaryocytes. The current study is the first to examine the effects of megakaryocytes from transgenic m...

Osteoporosis, characterized by low bone mineral density (BMD), is the most common complex disease affecting bone and constitutes a major societal health problem. Genome‐wide association studies (GWASs) have identified over 1100 associations influencing BMD. It has been shown that perturbations to long non‐coding RNAs (lncRNAs) influence BMD and the...

Objective Focal lesions within the subchondral bone, termed subchondral bone cysts (SBCs), are clinically accepted radiographic markers of advanced osteoarthritis (OA), but their etiology in the hip is not well understood. Design This study used micro-computed tomography (μCT), and histological and immunocytological analysis to examine the prevale...

Currently, there is no consensus whether there is a single or multiple postnatal stem cell population(s) that contribute to skeletal homeostasis and postnatal bone formation. A known population of cells that express Prx1 contributes to postnatal bone formation. Prx1 expression also connotes calvaria and appendicular tissues during embryonic develop...

Osteoarthritis (OA) is known to involve profound changes in bone density and microstructure near to, and even distal to, the joint. Critically, however, a full, spatial picture of these abnormalities has not been well documented in a quantitative fashion in hip OA. Here, micro-computed tomography (44.8 μm/voxel) and data-driven computational anatom...

Osteoporosis, characterized by low bone mineral density (BMD), is the most common complex disease affecting bone and constitutes a major societal health problem. Genome-wide association studies (GWASs) have identified over 1100 associations influencing BMD. It has been shown that perturbations to long non-coding RNAs (lncRNAs) influence BMD and the...

Time is a central element of the sexual dimorphic patterns of development, pathology and aging of the skeleton. Since the transcriptome is a representation of the phenome, we hypothesized that both sex and sex specific temporal, transcriptomic differences in bone tissues over an 18‐month period would be informative to the underlying molecular proce...

Genome-wide association studies (GWASs) for bone mineral density (BMD) have identified over 1,100 associations to date. However, identifying causal genes implicated by such studies has been challenging. Recent advances in the development of transcriptome reference datasets and computational approaches such as transcriptome-wide association studies...

GNAS encodes the stimulatory G protein alpha-subunit (Gsα) and its large variant XLαs. Studies have suggested that XLαs is expressed exclusively paternally. Thus, XLαs deficiency is considered to be responsible for certain findings in patients with paternal GNAS mutations, such as pseudo-pseudohypoparathyroidism, and the phenotypes associated with...

Bone loss is a major health concern for astronauts during long‐term spaceflight and for patients during prolonged bed rest or paralysis. Growing evidence suggests that osteocytes, the most abundant cells in the mineralized bone matrix, play a key role in sensing mechanical forces applied to the skeleton and integrating the orchestrated response int...

Bone is a complex, hierarchically organized organ system whose composition and structure are closely related to, and in many ways controlled by, the functional demands made upon it. Bone tissue is constantly undergoing turnover via coordinated activities by osteoblasts, osteoclasts, osteocytes, and their precursors. Through this process of bone rem...

The study of postnatal skeletal repair is of immense clinical interest. Optimal repair of skeletal tissue is necessary in all varieties of elective and reparative orthopedic surgical treatments. However, the repair of fractures is unique in this context in that fractures are one of the most common traumas that humans experience and are the end-poin...

The most common procedure that has been developed for use in rats and mice to model fracture healing is described. The nature of the regenerative processes that may be assessed and the types of research questions that may be addressed with this model are briefly outlined. The detailed surgical protocol to generate closed simple transverse fractures...

In the United States, 5-12% of adults have at least one symptom of temporomandibular joint (TMJ) disorders, including TMJ osteoarthritis (TMJ-OA). However, there is no chondroprotective agent that is approved for clinical application. We showed that LOXL2 is elevated in the regenerative response during fracture healing in mice and has a critical ro...

The osteoinductive property of strontium was repeatedly proven in the last decades. Compelling $\textit{in vitro}$ data demonstrated that strontium hydroxyapatite nanoparticles exert a dual action, by promoting osteoblasts-driven matrix secretion and inhibiting osteoclasts-driven matrix resorption. Recombinant human bone morphogenetic protein 2 (rh...

The osteoinductive property of strontium was repeatedly proven in the last decades. Compelling in vitro data demonstrated that strontium hydroxyapatite nanoparticles exert a dual action, by promoting osteoblasts-driven matrix secretion and inhibiting osteoclasts-driven matrix resorption. Recombinant human bone morphogenetic protein 2 (rhBMP2) is a...

Purpose of review: The failure of bony union following a fracture, termed a fracture nonunion, has severe patient morbidity and economic consequences. This review describes current consensuses and future directions of investigation for determining why, detecting when, and effective treatment if this complication occurs. Recent findings: Current...

Many scientific studies, especially in the biomedical sciences, generate data measured simultaneously over a multitude of units, over a period of time, and under different conditions or combinations of factors. Often, an important question of interest asked relates to which units behave similarly under different conditions, but measuring the variat...

Background: The goal of this study was to determine if adenovirus-delivered LOXL2 protects against progressive knee osteoarthritis (OA), assess its specific mechanism of action; and determine if the overexpression of LOXL2 in transgenic mice can protect against the development of OA-related cartilage damage and joint disability. Methods: Four-mo...

Transcriptomic analysis showed that the central circadian pathway genes had significantly altered expression in fracture calluses from mice fed a low phosphate diet. This led us to hypothesize that phosphate deficiency altered the circadian cycle in peripheral tissues. Analysis of the expression of the central clock genes over a 24-36 hour period i...

Motivation: Clustering algorithms like K-Means and standard Gaussian mixture models (GMM) fail to account for the structure of variability of replicated data or repeated measures over time. Additionally, a priori cluster number assumptions add an additional complexity to the process. Current methods to optimize cluster labels and number can be ina...

The retinoid X receptors (RXR), peroxisome proliferator activated receptor gamma (PPARγ) and liver X receptors (LXR) all have been shown to regulate bone homeostasis. Tributyltin (TBT) is an environmental contaminant that is a dual RXRα/β and PPARγ agonist. TBT induces RXR, PPARγ and LXR-mediated gene transcription and suppresses osteoblast differe...

A targeted proteomic analysis of murine serum over a 35-day course of fracture healing was carried out to determine if serum proteomic changes could be used to monitor the biological progression of fracture healing. Transverse, closed femoral fractures where generated and stabilized with intramedullary fixation. A single stranded DNA aptamer-based...

Activin A receptor type I or activin receptor-like kinase 2 (ACVRI/ALK2) belongs to type I TGF-β family and plays an important role in bone development. Activating mutations of ALK2 containing the R206 to H mutation, are present in 95% in the rare autosomal genetic diseasefibrodysplasiaossificansprogressiva (FOP), which leads to the development of...

Radiographic Union Score for Tibia (RUST) and modified RUST (mRUST) are radiographic tools for quantitatively evaluating fracture healing using a cortical scoring system. This tool has high intra-class correlation coefficients (ICCs); however, little evidence has evaluated the scores against the physical properties of bone healing. Closed, stabiliz...

Background Lysyl oxidase like-2 (LOXL2) is a copper-dependent amine oxidase. Our previous studies showed that LOXL2 is elevated during mouse fracture healing. The goal of this study was to evaluate the potential of LOXL2 to act as an anabolic agent in cartilage affected by osteoarthritis (OA). Methods LOXL2 was visualized in tissues from human kne...

Injury to the growth plate is associated with growth disturbances, most notably premature cessation of growth. The goal of this study was to identify spatial changes in the structure and composition of the growth plate in response to injury to provide a foundation for developing therapies that minimize the consequences for skeletal development. We...

Endochondral ossification is the process where cartilage forms prior to ossification and in which new bone forms during both fracture healing and ectopic bone formation. Transitioning to ossification is a highly coordinated process between hypertrophic chondrocytes, vascular endothelial cells, osteoblasts and osteoclasts. A critical biological proc...

Organotins are industrial chemicals and agricultural pesticides, and they contaminate both outdoor and indoor environments. Organotins are detectable in human sera at biologically active concentrations and are immuno-and neuro-toxicants. Triphenyltin, tributyltin (TBT) and dibutyltin activate peroxisome proliferator-activated receptor γ (PPARγ) in...

Phosphate plays a critical role in chondrocyte maturation and skeletal mineralization. Studies examining the consequences of dietary phosphate restriction in growing mice demonstrated not only the development of rickets, but also a dramatic decrease in bone accompanied by increased marrow adipose tissue (MAT). Thus, studies were undertaken to deter...

A soluble form of BMP receptor type 1A (mBMPR1A-mFC) acts as an antagonist to endogenous BMPR1A and has been shown to increase bone mass in mice. The goal of this study was to examine the effects of mBMPR1A-mFC on secondary fracture healing. Treatment consisted of 10mg/kg intraperitoneal injections of mBMPR1A-mFC twice weekly in male C57BL/6 mice....

Lysyl oxidases are required for collagen and elastin cross-linking and extracellular matrix maturation including in bone. The lysyl oxidase family consists of lysyl oxidase (LOX) and 4 isoforms (LOXL1-4). Here we investigate whether deletion of LOXL1, which has been linked primarily to elastin maturation, leads to skeletal abnormalities. Left femur...

Tributyltin Engages Multiple Nuclear Receptor Pathways and Suppresses Osteogenesis in Bone Marrow Multipotent Stromal Cells Catalog numbers and references for the primers used in qPCR analyses. Data include analyses of toxicity, of experiments investigating mixed exposures of agonists and antagonists, and of retinoic acid receptor-dependent gene e...

Organotins are members of the environmental obesogen class of contaminants because they activate peroxisome proliferator-activated receptor γ (PPARγ), the essential regulator of adipogenesis. Exposure to thiazolidinediones, PPARγ ligands used to treat type 2 diabetes, is associated with increased fractures. Diminished bone quality likely results fr...

Uncovering the mechanisms of the sensitivity of bone healing to mechanical factors is critical for understanding the basic biology and mechanobiology of the skeleton, as well as for enhancing clinical treatment of bone injuries. This study refined an experimental method of measuring the strain microenvironment at the site of a bone injury during bo...

Three commonly used murine surgical models of bone healing [closed fracture with intramedullary fixation, distraction osteogenesis (DO), and marrow ablation by reaming] are presented. Detailed surgical protocols for each model are outlined. The nature of the regenerative processes and the types of research questions that may be addressed with these...

Fractures are one of the most common large-organ, traumatic injuries in humans, and osteoporosis-related fractures are the fastest growing health care problem of aging. Elective orthopedic surgeries of the bones and joints also represent some of most common forms of elective surgeries performed. Optimal repair of skeletal tissues is necessary for s...

Tendon healing is characterized by the formation of fibrovascular scar tissue, as tendon has very little intrinsic regenerative capacity. This creates a substantial clinical challenge in the setting of large, chronic tears seen clinically. Interest in regenerative healing seen in amphibians and certain strains of mice has arisen in response to the...

Bone formation and aging are sexually dimorphic. Yet, definition of the intrinsic molecular differences between male and female multipotent mesenchymal stromal cells (MSC) in bone is lacking. This study assessed sex-linked differences in MSC differentiation in 3-, 6-, and 9-month-old C57BL/6J mice. Analysis of tibiae showed that female mice had low...

Aims/hypothesis: Diabetes interferes with bone formation and impairs fracture healing, an important complication in humans and animal models. The aim of this study was to examine the impact of diabetes on mesenchymal stem cells (MSCs) during fracture repair. Methods: Fracture of the long bones was induced in a streptozotocin-induced type 1 diabe...

While developmental processes usually terminate when animals reach maturity, morphogenetic processes may be reinitiated in specific tissues as a consequence of injury. Fracture healing and bone repair are among the unique processes of postnatal tissue regeneration that are believed to mirror the ontological events that take place during embryologic...

Fractures are the most common large-organ, traumatic injuries to humans. The repair of bone fractures is a postnatal regenerative process that recapitulates many of the ontological events of embryonic skeletal development. Although fracture repair usually restores the damaged skeletal organ to its pre-injury cellular composition, structure and biom...

Prior studies showed that loss of TNFα signaling delayed fracture healing by delaying chondrocyte apoptosis and cartilage resorption. Mechanistic studies showed that TNF-α induced Fas expression within chondrocytes; however, the degree to which chondrocyte apoptosis is mediated by TNFα alone or dependent on the induction of Fas is unclear. This que...

The study of postnatal skeletal repair is of immense clinical interest. Optimal repair of skeletal tissue is necessary in all varieties of elective and reparative orthopedic surgical treatments. However, the repair of fractures is unique in this context in that fractures are one of the most common traumas that humans experience and are the end-poin...

The most common procedure that has been developed for use in rats and mice to model fracture healing is described. The nature of the regenerative processes that may be assessed and the types of research questions that may be addressed with this model are briefly outlined. The detailed surgical protocol to generate closed simple transverse fractures...

The relationship between BMP2 expression and the recruitment of skeletogenic stem cells was assessed following bone marrow reaming. BMP2 expression was examined using transgenic mice in which β-galactosidase had been inserted into the coding region of BMP2. Stem cell mobilization was analyzed by FACS analysis using CD73 a marker associated with bon...

Runx2 and Runx3 are known to be expressed in the growth plate during endochondral bone formation. Here we addressed the functional role of Runx3 as distinct from Runx2 by using two models of post natal bone repair: fracture healing that proceeds by an endochondral process and marrow ablation that proceeds by only an intramembraneous process. Both R...

Each year in the United States, approximately 600,000 bone fractures show delayed or impaired healing and require subsequent surgical intervention1. Techniques for early identification of these cases are presently lacking but could make substantial impact on reducing the morbidity and costs associated with poor bone healing. A current barrier to ea...

Assessment of the early stages of fracture healing via X-rays and computed tomography is limited by the low radio-opacity of cartilage. We validated a method of contrast-enhanced computed tomography (CECT) for non-destructive identification of cartilage within a healing fracture callus. Closed, stabilized fractures in femora of C57BL/6 mice were ha...

Vascular endothelial growth factor (VEGF) is an endothelial cell survival factor and is required for effective coupling of angiogenesis and osteogenesis. Although central to bone homeostasis, repair and the pathobiology that affect these processes, the precise mechanisms coupling endothelial cell function within bone formation and remodelling remai...

Chemokines are thought to play an important role in several aspects of bone metabolism including the recruitment of leukocytes and the formation of osteoclasts. We investigated the impact of diabetes on chemokine expression in normal and diabetic fracture healing. Fracture of the femur was performed in streptozotocin-induced diabetic and matched no...

Donor site morbidity and limited volume remain primary drawbacks of using bone graft from the iliac crest and an impetus for finding other sources of autologous bone-graft material. The Synthes Reamer/Irrigator/Aspirator (RIA) has been found to have value as an autologous bone-graft harvesting device. The purpose of this study was to compare the ce...

Vascular formation is intimately associated with bone formation during distraction osteogenesis (DO). While prior studies on this association have focused on vascular formation locally within the regenerate, we hypothesized that this vascular formation, as well as the resulting osteogenesis, relies heavily on the response of the vascular network in...

The differentiation of osteoblasts from their precursors, mesenchymal stem cells, is an important component of bone homeostasis as well as fracture healing. The A2B adenosine receptor (A2BAR) is a Gα(s)/α(q)-protein-coupled receptor that signals via cAMP. cAMP-mediated signaling has been demonstrated to regulate the differentiation of mesenchymal s...

Prior studies showed that bone regeneration during distraction osteogenesis (DO) was dependent on vascular tissue development and that inhibition of VEGFR signaling diminished the expression of BMP2. A combination of micro-computed tomography (μCT) analysis of vascular and skeletal tissues, immunohistological and histological analysis of transgenic...