Hiroshi Kawaguchi, MD, PhD; Toru Akune, MD, PhD; Takashi Yamada, MD, PhD; and Naoshi Ogata, MD, PhD—all of the department of orthopaedic surgery, faculty of medicine, at the University of Tokyo—submitted the winning paper, “Mouse genetics studies on molecular mechanism underlying bone and cartilage disorders.”
Published 3/1/2003
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Mary Ann Porucznik
Genetic studies shed light on musculoskeletal conditions
The prevalence of bone and cartilage disorders increases with age, but aging alone doesn’t explain their development. By studying mouse genetics, the winners of the Kappa Delta Ann Doner Vaughan Award hoped to clarify the molecular background of several degenerative skeletal disorders, including osteoporosis, ossification of the posterior longitudinal ligament of the spine (OPLL), bone fracture healing, and osteoarthritis (OA).
Hiroshi Kawaguchi, |
“The ultimate aim of these mouse genetics studies is to identify the molecular targets for clinical treatments of the bone and cartilage disorders,” they wrote. “Based on the findings obtained, we have attempted to confirm the reproducibility of the mouse findings in humans using human genomic or biochemical studies.”
From osteoporosis to osteoarthritis
An analysis of mice deficient in PPARγ, a key molecule intrinsic to bone marrow progenitors, revealed the involvement of the PPARγ signal in the pathophysiology of age-related osteoporosis.
The investigators then examined the role of insulin and insulin-like growth factor-I (IGF-I) signals in age-related osteoporosis. Insulin/IGF-I is positively correlated with ossification extent of OPLL patients and bone density of aged populations, making them ideal candidates for regulating OPLL and age-related osteoporosis. Studies on insulin receptor substrate (IRS) molecules IRS-1 and IRS-2 identified the potential role of these molecules in bone turnover and remodeling. They found that “insulin and IGF-I may up-regulate bone formation without affecting bone resorption through the balance of the two IRS signals in osteoblasts.”
The two IRS molecules also play a role in bone formation and healing, according to the researchers. Their study of bone healing found that fractures in mice deficient in IRS-1 did not heal properly. “Contrarily, the fracture healing was not suppressed in IRS-2 deficient mice,” they wrote.
Other studies in the report focused on the role of the Runx2 transcriptional activator in the regulation of cartilage degradation in osteoarthritis. In comparing the progression of OA in wild-type mice and in heterozygous Runx2-deficient mice, researchers found that “cartilage degradation in heterozygous Runx2-deficient mice was much milder than that of the wild-type mice at 8 weeks and thereafter.”
Further studies on pro-inflammatory factors convinced the researchers that “inflammation may be associated with the OA process as a consequence, but might not have a central role in the cause of OA initiation or progression.”
Additional findings indicate that carminerin, a novel molecule also called cystatin 10, may contribute to osteophyte formation without affecting cartilage degradation, and that carminerin deficiency may impair endochondral ossification by suppressing chondrocyte calcification.
Current research
“One of the next tasks ahead of us will be to elucidate the network system of these many factors,” concluded the researchers. “Among the molecules we identified in this study are some whose suppression ameliorated skeletal disorders under pathological conditions but did not affect physiological conditions, indicating that targeting these molecules may lead to an ideal treatment without side effects on physiological functions. In fact, trials based on the present findings are being practically planned for clinical application.”
The researchers received funding from several government and research foundations, including an unrestricted research grant from Bristol-Myers Squibb/Zimmer.