Disruptions in TGFβ Signaling Alters Sclerostin Expression and Load-Mediated Bone Formation (S. Tang, University of California, San Francisco)
PTHrP Regulates the Modeling of Entheses During Growth (M. Wang, Yale University)
High-Resolution Magnetic Resonance Imaging to Assess Bone Microarchitecture and Mechanical Properties in Vivo (G. Chang, NYU Langone Medical Center)
Stem Cell Mobilization to Enhance Bone Regeneration (M. McNulty, Rush University Medical Center)
Estrogen Receptor Alpha is Critical to the Anabolic Response of Cancellous and Cortical Bone to Mechanical Load (R. Main, Purdue University)
Epidermal Growth Factor Receptor Regulates Cartilage Matrix Remodeling During Endochondral Ossification through –β-catenin-dependent and independent Pathways (X. Zhang, University of Pennsylvania)
Crosstalk Between Parathyroid Hormone Related Protein and Minor Fibrillar Collagens (M. Hiremath, Boise State University)
Suppressive Effects of BRD4 Inhibitor on Inflammatory Cytokine Expression and RANKL-Induced Osteoclastogenesis (S. Meng, Tufts University)

Additional ASBMR/ Harold M. Frost Young Investigator Award Winner presenting in another session:
A. Das, University of Viriginia: Presenting in session: Principles of Engineering Tissue Regeneration:Local Delivery of Sphingosine1- Phosphate Receptor Specific Small Molecules in Nanofiber Scaffolds Enhance Mandibular Defect Healing by Recruiting Progenitor Cells and Increasing Vascularization

This session investigates several novel functions of osteocytes in interaction with muscle during age-related declines, coordination of bone resorption through the RANKL/OPG system, and as mediators in the connection between hormonal regulation and bone formation. Our understanding of the contribution of osteocytes to these systems has been expanded greatly in the past few years, and these novel functions will be explored in this session. The session will also include new data from two young investigators who will receive awards for their outstanding research during the Workshop.

Update on Osteocytes
Overview of osteocyte function and interactions with muscle (L. Bonewald, Univ Missouri- Kansas City) Recent research has shown that osteocytes are major regulators of the function of osteoblasts and osteoclasts and may play a centralized role in regulating bone mass. Osteocytes also appear to act as endocrine factors targeting other organs such as kidney, the immune system, and others. While dogma assumes that the muscle-bone relationship is driven purely by mechanical factors, bone can act, in effect, as an “endocrine organ” to control muscle physiology and disease.The traditional view of skeletal muscle and bone interaction is that skeletal muscle loads bone and bone provides an attachment site for muscle. This mechanical perspective implies that as muscle function declines, this would result in decreased loading of the skeleton and therefore would result in a decrease in bone mass. However, muscle atrophy alone cannot fully explain the totality of osteoporosis and, reciprocally, aging associated decreases in bone mass do not fully explain sarcopenia. We have begun to examine the molecular and cellular mechanisms that contribute to the coordinated development of bone and muscle conditions. With age, a factor produced by muscle and which acts on the osteocyte and enhances both its viability and ability to respond to exercise, is no longer being made. Identification of this factor is in process.

Osteocyte regulation of osteoclastic bone resorption through RANK/OPG expression (H Takayanagi, Tokyo Medical and Dental University) Osteocytes are thought to orchestrate bone homeostasis by regulating both bone-forming osteoblasts and bone-resorbing osteoclasts. It is well know that osteoclast differentiation and function is regulated by receptor activator NF-κB ligand, RANKL. Previously it was assumed that RANKL was mainly expressed by osteoblasts or stromal cells in bone marrow. We showed that osteocytes within the bone matrix are the critical source of RANKL, that osteocytes express five times greater amounts of RANKL than osteoblasts, and that targeted deletion of RANKL in osteocytes results in a severe osteopetrotic phenotype. Therefore a major means by which the osteocyte regulates osteoclastic bone resorption is through the expression of RANKL.

PTH, the master regulator of osteocyte function (T. Bellido, Indiana University) The discovery that parathyroid hormone (PTH), a central regulator of bone homeostasis, inhibits the expression of sclerostin, the osteocyte-produced inhibitor of bone formation, initiated a cascade of studies that had revealed that osteocytes are crucial target cells of the actions of PTH. Transgenic mice expressing a constitutive active PTH receptor (PTHR1) in osteocytes exhibit reduced sclerostin expression and increased bone mass; and bone anabolism in this model strictly depends on downregulation of sclerostin. Unexpectedly, activation of PTHR1 signaling in osteocytes also increases RANKL expression and bone resorption; and the converse effect is found in mice lacking PTHR1 in osteocytes. However, control of osteoclast generation and resorption does not depend on sclerostin downregulation, demonstrating that PTH acts on osteocytes to regulate bone formation and resorption by separate mechanisms. PTHR1 signaling also increases the expression of FGF23, an osteocyte product that inhibits phosphate re-absorption in the kidney and regulates matrix mineralization. The FGF23 receptor complex (FGFR1/Klotho) is expressed in osteocytes and osteoblasts, and FGF23 signaling is enhanced in bone by PTHR1 activation. Thus, regulation of osteocytic FGF23 by PTH might modulate mineral homeostasis by endocrine as well as auto/paracrine mechanisms. Signaling downstream of the PTHR1 in osteocytes also cross-talks with mechanotransduction, as evidenced by a deficient response to loading of mice lacking the PTHR1 in osteocytes. These findings demonstrate that direct actions PTH on osteocytes regulate the expression of genes that impact skeletal homeostasis and suggest that the PTH receptor expressed in osteocytes participates also in the coordinated regulation of bone formation by hormonal and mechanical stimuli.