Dept. of Oral & Maxillofacial Surgery
School of Dentistry
Government College, Sahiwal, Pakistan
BSc, Botany, Zoology, Chemistry, Geography, 1987
University of the Punjab, Lahore, Pakistan
MSc, Cell Biology, 1990
University of the Punjab, Lahore, Pakistan and
UMass Medical School, Worcester, MA
PhD, Cell and Molecular Biology, 2000
Genetic Control of Skeleton Formation and Remodeling During Development and Aging
The central focus of our laboratory is to understand the molecular mechanisms that govern the formation and remodeling of skeletal tissues such as Cartilage, Bone, Teeth and Tendon. Cellular differentiation involves the stepwise establishment of specific genetic programs in proliferating cell lineages. We are exploring the signaling role of runt related transcription factor (Runx), in the coordinated regulation of various cell types (Chondrocyte, Osteoblast, Odontoblast) during skeletogenesis. Runx factors are heterodimers formed by α and β subunit and are essential for embryonic development. In mammals three genes encode α subunits (Runx1, 2 and 3) that heterodimerise with the common β subunit. All three gene products recognize the same DNA sequences, but exhibit distinct and non-redundant biological functions. Runx1 is required for definitive hematopoiesis and is frequently mutated in human leukemia. Runx2 is required for osteogenesis and in human mutations of the Runx2 gene are associated with cleidocranial dysplasia, an autosomal dominant skeletal disorder characterized by clavicular and pelvic anomalies, multiple supernumerary teeth, and a sever delay in closure of the fontanels. Runx3 controls neurogenesis, development and proliferation of the gastric epithelium and is frequently silenced in human gastric cancer.
Throughout our life, bone is constantly renewed via a two-part process called remodeling. This process consists of bone resorption and bone formation. During resorption, old bone tissue is broken down and removed by special cells called osteoclasts. During bone formation, new bone tissue is laid down to replace the old. This task is performed by special cells called osteoblasts. Osteoclast and osteoblast function is regulated by several genes and hormones such as calcitonin, parathyroid hormone, vitamin D, estrogen (in women) and testosterone (in men), among others. Runx2 transcription factor is required for normal differentiation and hormonal responsiveness of the Ostoblasts. Our lab utilizes biochemical, cellular, genetic and molecular approaches to identify molecular pathways that conveys osteogenic signal to Runx2 for formation and activity of bone cell.
Runx2 knock-in and knock-out mouse models show a complete absence of both intramembranous and endochondral ossification and dies in utero or shortly after birth.
Because of embryonic lethality current models are useless to address Runx2 role in bone formation, remodeling and repair in adults. To circumvent this difficulty we have developed mouse model where Runx2 gene can be inactivated in adults in a spatiotemporal fashion. We are directing our efforts towards understanding of specific roles of Runx2 gene during post-natal bone formation, bone remodeling, fracture healing, osteoporosis, autoimmune diseases (lupus, psoriasis, rheumatoid arthritis) and aging.
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