Faculty Homepage:	Divisional Home Page
Email:	jrubin@med.unc.edu
Appointments:	Professor, Division of Endocrinology/Metabolism Department of Medicine Professor in Pharmacology and Pediatrics Adjunct Professor, Bioengineering
Room:	5032 Burnett Womack
Phone:	919-966-6744 clinic patients use 919-484-1015

Skeletal Research

The skeleton is a complex tissue that is able to regulate its own mass and architecture to meet two critical and competing responsibilities: one structural and the other metabolic. The structure of bone is determined largely through its ability to respond to daily loading with intelligent remodeling. When mechanical signals are suppressed (no exercise, space travel, getting old) bone structure degenerates - and bone resorption outpaces bone formation.  If skeletal degeneration is severe it will lead to catastrophic failure with fracture.  Alternatively, daily skeletal loading leads to bone formation, enhancing not only the activity of bone osteoblasts to make new bone, but also promotes the entry of mesenchymal stem cells into the osteogenic lineage.  Our cellular and molecular biological investigations are aimed at understanding mechanical and hormonal control of bone remodeling.

Our current focus is to understand the role of biophysical forces experienced by the skeleton during exercise, in controlling bone remodeling.   We are interested in signaling events that enhance osteoblast activity - in particular the ability of mechanical factors to activate β-catenin and MAPK/HRas.  Both signaling molecules appear to have regulatory roles not only in promoting bone formation and inhibiting bone resorption, but also in preventing mesenchymal stem cell entry into the adipocyte lineage.  Eventually we hope to be able to apply this understanding to improving bone structure by using non-pharmacologic mechanical/exercise strategies to promote bone cell function.

In the laboratory we apply mechanical signals to cells supplying bone, including strain, shear, and most recently, low intensity vibration.  These cells, including mesenchymal stem cells, adipocytes and osteoblasts, sense and respond to mechanical input, causing alterations in gene expression, differentiation and functional phenotype.  Some gene responses that we study (RANKL, osterix, RUNX2, eNOS) require activation of ERK1/2 activation by strain/shear and occur many hours after mechanical activation.  Other genes respond much more quickly (COX2, cyclin D1, WISP1) and require activation of beta-catenin.  We believe that the integration of these two pathways results in the "loaded response"- i.e., a positive enhancement of bone structure.  Whether the same response controls the allocation of stem cells into bone or fat lineage is also a major investigative topic in the lab in 5030 Burnett-Womack, UNC.

Current members of our lab include:

• William Thompson PhD
• Buer Sen MD
• Zhihui Xie MD
• Maya Styner MD (Endocrine faculty)
• Kornelia Gailor
• Natasha Case PhD  (also member of Dr Farshid Guilak's laboratory at Duke)

Previous members have included Jacob Thomas, Emily Neely MD, James Meeker MD, Meiyun Ma MD, Minxou Zou MD, and Chris O'Conor (Guilak lab/Duke).

Click here to see some of us in the lab: Rubin Lab Folks

We are grateful to NIAMS for our NIH support.

Essential collaborations continue with:

• Dr. Clinton Rubin, Musculoskeletal Research, SUNY
• Dr. Ted Gross, Orthopedics, University of Washington
• Dr. Mark Horowitz, Orthopaedics, Yale University

I am forever in debt to my colleagues at Emory/VAMC in Atlanta (2006!), including Dr. Xian Fan, Tamara Murphy and Jill Rahnert.

Recent Publications

1.  Sen B, Xie Z, Case N, Ma, M, Rubin CT, Rubin J 2008 Mechanical strain inhibits adipogenesis in mesenchymal stem cells by stimulating a durable β-catenin signal.  Endocrinology 149:6065-75

2.  Ozcivici E, Luu YK, Adler B, Qin Y, Rubin J, Judex S, Rubin CT  2010 Mechanical signals as anabolic agents in bone, Nature Reviews in Rheumatology, 6:50-59.

3.  Sen B, Styner M, Xie Z, Case N, Rubin CT, Rubin J 2009 Mechanical loading regulates NFATc1 and b-catenin signaling through a GSK3b control node, J Biological Chemistry, 284:34607-34617

4.  Case N, Zou M, Xie Z, Sen B, Styner M, O’Conor C, Horowitz M, Rubin J 2010 Mechanical activation of β-catenin regulates phenotype in adult murine marrow-derived mesenchymal stem cells. J Orthop Res. 28(11):1531-8.

5.  Case N and Rubin J 2010 Prospects: β-catenin – a supporting role in the skeleton, J Cell Biochem. 110(3):545-53.

6.  Styner M, Sen B, Xie Z, Case N, Rubin J 2010 Indomethacin promotes adipogenesis from MSC through PG independent mechanisms, J Cell Biochem. 111(4):1042-50

7.  Sen B, Styner M, Xie Z, Case N, Rubin CT, Rubin J 2011 Mechanical inhibition of adipogenesis achieved via a regenerated β-catenin signal is amplified by incorporating a refractory period, Journal of Biomechanics, in press

8.  Gourlay ML, Preisser JS, Hammett-Stabler CA, Rubin J 2011 Follicle stimulating hormone is less important than weight and race in determining bone density in younger postmenopausal women, Osteoporosis Int 22:2699-708

9.  Sen B, Guilluy C, Xie Z, Case N, Styner M, Thomas J, Oguz I, Rubin C, Burridge K, Rubin J, 2011 Mechanically induced focal adhesion assembly amplifies anti-adipogenic pathways in mesenchymal stem cells Stem Cell 29:1829–1836

10.  Case N, Thomas J, Sen B, Styner M, Xie Z, Galior K, Rubin J Mechanical activation of Akt via serine 473 phosphorylation requires mTORC2 in MSC  in press J Biological Chemistry