Written by Chrystal Moulton, Staff Writer. DPP4 is a potential osteoclast-osteoblast coupling factor; treatment with DMAb improved glycemic control in diabetic participants with osteoporosis.
Bone remodeling is a vital part of skeletal health and growth 1,2. Normally, osteoclasts digest old bone tissue followed by the reforming of bone tissue by osteoblasts in a coupled reaction. However, certain diseases like osteoporosis leads to an excess of bone resorption contributing to bone loss and fracture 1,2. Osteopetrosis, on the other hand, is characterized by high bone mass due to mutation in osteoclast differentiation or function. Patients with this disease have brittle bones. In both diseases the required coupling reaction between osteoclasts and osteoblasts is needed for skeletal health 3. Anti-resorptive therapies are the first line of treatment for osteoporosis 4 which lower the number of osteoclasts and slow down removal of old tissue. However, the decrease in the number of osteoclasts also leads to a decrease in osteoblasts thus limiting the effectiveness of anti-resorptive therapies 5. The same result is observed in patients with osteopetrosis: the defect in osteoclast differentiation leads to a low count in osteoclasts and subsequently a decrease in the number of osteoblasts. Osteopetrosis affecting osteoclast activity, however, does not affect osteoblast numbers and maintains bone formation rates 3. In order to identify factors linking osteoclast and osteoblast activity, researchers in the current trial treated post-menopausal women using denosumab [DMAb] (an antiresorptive pharmaceutical drug) to pharmacologically reduce the number of osteoclasts and investigate the reaction through a series of tests 6.
Fifty-six post-menopausal women were recruited for a one-time treatment with denosumab [DMAb] or placebo. Participants were randomly assigned to each protocol and followed up after 3 months. In the end, data from 24 participants in each group was used for this analysis. Needle bone biopsy as well as peripheral blood serum and bone marrow plasma was collected and analyzed for participants in each treatment arm three months after treatment. These samples were used to identify gene signatures of osteoclast and osteoblast cells and evaluate correlation between gene sets and functional bone data.
After three months, researchers observed a significant reduction in serum markers of bone resorption (C-terminal telopeptide of type one collagen or CTX and tartrate-resistant acid phosphatase 5B or TRAP5b) and decrease in serum markers of bone formation (procollagen type 1 N-terminal propeptide or P1NP and osteocalcin or OCN). Serum markers of bone resorption (CTX and TRAP5b) correlated significantly with serum markers of bone formation (P1NP and OCN) [CTX: P1NP, R = 0.72, P <0.001; CTX: OCN, R = 0.72, P <0.0001] [TRAP5b: P1NP, R = 0.43, P = 0.002; TRAP5b: OCN, R = 0.31, P = 0.031]. Bone samples biopsied from the participants were also homogenized for RNA isolation. Researchers observed a strong correlation in the coupling of osteoclast and osteoblast at the genetic level (R = 0.75, P= 0.002). Eight gene sets were accepted as markers of osteoclast and osteoblast lineage. To observe the correlation between gene sets and systemic markers of bone are modeling, researchers compared osteoblast genes downregulated by denosumab [DMAb] compared to serum markers from placebo participants. Results showed that osteoblast genes downregulated by DMAb was positively correlated with CTX and P1NP in placebo participants. Further analysis of bone marrow plasma and needle biopsy samples revealed that LIF, CST3, CCBE1, CREG2, and DPP4 are likely osteoclast-specific factors downregulated by DMAb that are potentially involved in coupling reactions between osteoclasts and osteoblasts in humans. DPP4, a target for diabetes therapy, when inhibited prevents inactivation (or increases) glucagon-like peptide-1 (GLP-1) leading to increase in insulin synthesis and secretion as well as a decrease in plasma glucose. DPP4 transcript was found in osteoclasts and the subsequent treatment with DMAb increased glucagon-like peptide-1 (GLP-1) in participants. Researchers then evaluated a group of diabetic patients treated with DMAb versus bisphosphonate or calcium plus vitamin D for one year. They observed a greater decrease in HbA1c in DMAb group compared to both the bisphosphonate and calcium plus vitamin D alone group after 12 months (P <0.00001 and P<0.01 respectively). Thus, diabetic patients with osteoporosis that were treated with the DMAb had significant improvement in glycemic control.
Overall researchers were able to identify 5 coupling factors that are potentially involved in bone remodeling. Among these factors, DPP4 is also implicated as a target therapy for diabetes. Therefore, diabetic osteoporosis patients treated with antiresorptive therapies like DMAb can also benefit from the glycemic control it provides. More research is needed to validate these findings.
Source: Weivoda, Megan M., Chee Kian Chew, David G. Monroe, Joshua N. Farr, Elizabeth J. Atkinson, Jennifer R. Geske, Brittany Eckhardt et al. “Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism.” Nature communications 11, no. 1 (2020): 1-13.
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Posted September 2, 2021.
Chrystal Moulton BA, PMP, is a 2008 graduate of the University of Illinois at Chicago. She graduated with a bachelor’s in psychology with a focus on premedical studies and is a licensed project manager. She currently resides in Indianapolis, IN.
References:
- Parfitt, A. Michael. “The coupling of bone formation to bone resorption: a critical analysis of the concept and of its relevance to the pathogenesis of osteoporosis.” (1982): 1-6.
- Martin, T. John, and Natalie A. Sims. “Osteoclast-derived activity in the coupling of bone formation to resorption.” Trends in molecular medicine2 (2005): 76-81.
- Sobacchi, Cristina, et al. “Osteopetrosis: genetics, treatment and new insights into osteoclast function.” Nature Reviews Endocrinology9 (2013): 522-536.
- Reginster, Jean-Yves. “Antifracture efficacy of currently available therapies for postmenopausal osteoporosis.” Drugs1 (2011): 65-78.
- Khosla, Sundeep, Jennifer J. Westendorf, and Merry Jo Oursler. “Building bone to reverse osteoporosis and repair fractures.” The Journal of clinical investigation2 (2008): 421-428.
- Weivoda, Megan M., et al. “Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism.” Nature communications1 (2020): 1-13.
