Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Abstract

Objective: Age-related bone loss is associated with significant changes in bone remodeling characterized by decreased trabecular and periosteal bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Prevention or reversal of age-related decrease in bone mass and increase in bone fragility has been based on inhibition of bone resorption using anticatabolic drugs. The current challenge is to promote osteoblastogenesis and bone formation to prevent age-related bone deterioration. Methods: A limited number of approved therapeutic molecules are available to activate bone formation. Therefore, there is a need for anabolic drugs that promote bone matrix apposition at the endosteal, endocortical, and periosteal envelopes by increasing the number of osteoblast precursor cells and/or the function of mature osteoblasts. In this study, we review current therapeutics promoting bone formation and anabolic molecules targeting signaling pathways involved in osteoblastogenesis, based on selected full-text articles searched on Medline search from 1990 to 2010. Results and discussion: We present current therapeutic approaches focused on intermittent parathyroid hormone and Wnt signaling agonists/antagonists. We also discuss novel approaches for prevention and treatment of defective bone formation and bone loss associated with aging and osteoporosis. These strategies targeting osteoblastic cell functions may prove to be useful in promoting bone formation and improving bone strength in the aging population.

Pharmacological inhibition of PPARγ increases osteoblastogenesis and bone mass in male C57BL/6 mice

“…The majority of these new treatments have been directed at inhibition of bone resorption, whereas anabolic compounds in use or under investigation remain scarce. (1,3) An effective bone anabolic agent would induce bone formation by stimulating osteoblast activity, by protecting osteoblasts against premature death, and by promoting the differentiation of MSC down the osteoblast rather than the adipocyte lineage. (1) In fact, several studies have demonstrated that it is possible to stimulate osteoblast differentiation at the expense of adipogenesis using compounds such as parathyroid hormone, (18) interferon gamma, (19,20) and strontium ranelate.…”

“…(1,3) An effective bone anabolic agent would induce bone formation by stimulating osteoblast activity, by protecting osteoblasts against premature death, and by promoting the differentiation of MSC down the osteoblast rather than the adipocyte lineage. (1) In fact, several studies have demonstrated that it is possible to stimulate osteoblast differentiation at the expense of adipogenesis using compounds such as parathyroid hormone, (18) interferon gamma, (19,20) and strontium ranelate. (21) The active metabolite of vitamin D, 1,25(OH) 2 D 3 , has also been shown to stimulate bone formation by promoting osteoblastogenesis (12) and inhibiting adipogenesis (17) in a murine model of age-related bone loss.…”

“…(1,3) One of the approaches to increase bone formation is to stimulate the differentiation of mesenchymal stem cells (MSC) into osteoblasts. (1,4) The progressive accumulation of marrow fat is one of the invariable features of age-related bone loss and osteoporosis in older persons, (5) which is the result of a shift in the differentiation program of MSC from osteogenic in young bone into adipogenic in older bone. (6) This switch in the differentiation program is associated with age-related changes in the expression of transcription factors including the widely described reduction in expression of the osteogenic runt-related transcription factor 2 (Runx2) and increased expression of the adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARg).…”

“…The objective of the current study was to determine if BADGE alone, or in combination with the bone anabolic agent 1,25 dihydroxy-vitamin D3 (1,25[OH] 2 D 3 ), (12) could promote bone formation in skeletally mature mice by binding to and inhibiting the activity of PPARg. The results demonstrate that pharmacological inhibition of PPARg could become a useful anabolic treatment for osteoporosis.…”

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

“…Dysregulations of osteoclast and osteoblast activities are associated with a range of pathological diseases such as osteoporosis which is characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility [20,21]. Due to the increasing need for anabolic therapies to prevent age-related bone loss, research has been focused over the last decade on molecular mechanisms regulating osteoblast function in postnatal remodeling [20][21][22]. For instance, Runx2 and Osx have been found to regulate osteoblast function in adult bone in addition to their primarily established role in osteoblastogenesis [23,24].…”