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Joseph Stains, Ph.D.
Assistant Professor,
Department of Orthopaedics
University of Maryland
School of Medicine
20 Penn Street HSFII, S005
Baltimore, MD 21201
410-706-2494
410-706-0028 fax
jstains@umoa.umm.edu
Bone remodeling is a dynamic process that requires coordinated cellular activities among osteoblasts, osteocytes and osteoclasts to maintain bone homeostasis. The cooperative nature of both bone modeling and remodeling requires tightly regulated mechanisms of intercellular recognition and communication that permit the cells to sort and migrate, synchronize activity, equalize hormonal responses, and diffuse locally generated signals. One mechanism by which osteoblasts and osteocytes achieve these interactions is via the formation of communicative gap junctions. Bone forming osteoblasts are highly coupled by gap junctions formed primarily by connexin43 (Cx43). The resulting gap junctions permit the diffusion of molecules less than 1000 Da, including metabolites, ions and second messengers such as inositol derivatives and cAMP.
The loss or mutation of connexins is a mechanism of disease in many tissues. In the skeleton, at least 24 separate mutations in the Cx43 gene results in oculodentodigital dysplasia (ODDD). This rare condition in humans results in abnormalities in craniofacial development, limbs and dentition. The skeletal phenotype of the affected patients includes syndactyly of the hands and foot, hypoplasia or aplasia of the middle phalanges, cranial hyperostosis, a widened alveolar ridge of the mandible, and broad tubular bones. The dentition of ODDD patients exhibit microdontia, anodontia, and enamel hypoplasia. These skeletal phenotypes are similar though not identical to that of the Cx43 null mice. Mice in which Cx43 has been genetically deleted are born with hypomineralization of craniofacial bones, and exhibit a severe delay in ossification of the axial and appendicular skeleton, and the osteoblast isolated from the calvaria of Cx43 deficient mice have a diminished osteogenic differentiation and mineralization potential, characterized by a reduction in gene expression of osteocalcin, type I collagen, and bone sialoprotein – three critically important bone extracellular matrix proteins.
Like osteoblasts, synovial cells are also coupled by gap junctions composed of Cx43. A series of recent reports has implicated the increase in gap junctional coupling mediated by Cx43 with the up-regulation of matrix metalloproteinase production during osteoarthritis (OA). The synovial cells isolated from these patients possess increased Cx43 expression and gap junctional coupling and also produced increased amounts matrix metalloproteinases (MMPs). MMPs, which control the breakdown of the underlying articular cartilage, are a likely therapeutic target in treating OA. In fact in these studies, disruption of gap junctional communication was demonstrated to prevent this increase in MMP production.
My laboratory is interested in investigated the molecular mechanisms of intercellular communication. Our primary focus has been on the role of gap junction proteins, connexins, in regulating cellular function. We have demonstrated that disruption of gap junctional coupling among osteoblasts results in a dramatic downregulation of critical osteoblastic genes. This dysregulation of osteogenesis is a result of attenuation of signal molecules propagated via the gap junction channels to adjacent cells. Using molecular and cell biological approaches we will pursue the mechanisms by which gap junctions propagate signals to activate signal transduction cascades that lead to transcriptional changes that affect cell function.
Our current projects are directed towards:
For more information about the University of Maryland Orthopaedics Musculoskeletal Research Laboratories, please call (410) 706-2417.
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