BoneKEy-Osteovision | Not To Be Missed

Clinical and basic research papers: November and December 2003 selections

DOI:10.1138/20040126

Bone modeling and remodeling

◆ Holmbeck K, Bianco P, Chrysovergis K, Yamada S, Birkedal-Hansen H. MT1-MMP-dependent, apoptotic remodeling of unmineralized cartilage: a critical process in skeletal growth. J Cell Biol. 2003 Nov 10;163(3):661–71.

Recommended.

◆ Metz LN, Martin RB, Turner AS. Histomorphometric analysis of the effects of osteocyte density on osteonal morphology and remodeling. Bone. 2003 Nov;33(5):753–9.

This is an interesting study of osteocytes in which the data support the authors’ novel hypothesis that osteocytes contribute to the regulation of osteon morphology. High osteocyte density increases osteon porosity by reducing the rate of refilling, formation period, and wall width.

◆ Misof BM, Roschger P, Tesch W, Baldock PA, Valenta A, Messmer P, Eisman JA, Boskey AL, Gardiner EM, Fratzl P, Klaushofer K. Targeted overexpression of vitamin D receptor in osteoblasts increases calcium concentration without affecting structural properties of bone mineral crystals. Calcif Tissue Int. 2003 Sep;73(3):251–7.

Whole bone strength is modified through changes in material and structural properties. There are many examples of the latter. In this study, overexpression of vitamin D receptor in osteoblasts increased the tissue mineral density and homogeneity of distribution of mineral in primary spongiosa. The mutant displayed other interesting phenotypic differences, compared with the wild-type.

◆ Olmsted-Davis EA, Gugala Z, Camargo F, Gannon FH, Jackson K, Kienstra KA, Shine HD, Lindsey RW, Hirschi KK, Goodell MA, Brenner MK, Davis AR. Primitive adult hematopoietic stem cells can function as osteoblast precursors. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15877–82.

Transplantation of a defined population of self-replicating hematopoietic stem cells can populate metaphyseal bone with large numbers of osteoblasts; diaphyseal bone contains fewer donor osteoblasts. Osteoblast precursors are identifiable after transplantation of a single cell. Rare events, such as fusion with recipient osteoblast precursors, are possible explanations of the result, but seem unlikely. Can this phenomenon explain the surprising response of osteogenesis imperfecta to bone marrow transplantation? —GJS

Genetics

◆ Klein RF, Allard J, Avnur Z, Nikolcheva T, Rotstein D, Carlos AS, Shea M, Waters RV, Belknap JK, Peltz G, Orwoll ES. Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science. 2004 Jan 9;303(5655):229–32.

In a remarkable publication,Alox15, which encodes a lipoxygenase, was identified in a quantitative trait locus (QTL) interval for low bone mass and shown to be directly involved in the control of bone mass, using genetic methods and two pharmacological inhibitors of enzyme activity. The QTL strategy has yielded an osteoporosis gene that promises to be an important therapeutic target. —GJS

Pathophysiology

◆ Shao JS, Cheng SL, Charlton-Kachigian N, Loewy AP, Towler DA. Teriparatide (human parathyroid hormone (1-34)) inhibits osteogenic vascular calcification in diabetic low density lipoprotein receptor-deficient mice. J Biol Chem. 2003 Dec 12;278(50):50195–202.

Low-density lipoprotein receptor-deficient mice fed high-fat diabetogenic diets develop atherosclerosis and vascular calcification. Vascular calcification is blocked by administration of a once-daily parathyroid hormone (1-34) (PTH[1-34]) regimen that increases bone mass. PTH inhibits mineralization induced by MSX in cultured aortic myofibroblasts. Serum levels of osteopontin (OPN) are significantly increased by PTH treatment, but vascular expression of OPN is reduced, and OPN is proposed to be one mediator of PTH effects, but an opposite view of the role of OPN has also been published (Bruemmer, et al. Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice. J. Clin. Invest. 2003 Nov 1; 112 (9) : 1318–1331). In dialysis patients, atherosclerosis is accelerated by secondary hyperparathyroidism; would continuous PTH protect against or accelerate calcification in the mouse model? —GJS

◆ Stenderup K, Justesen J, Clausen C, Kassem M. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone. 2003 Dec;33(6):919–26.

Bone “loss” may refer to loss of mineral mass, bone mass, or both. Bone loss may be due to high remodeling alone (loss of mineral only) or due to a greater volume of bone resorbed and/or less bone formed in the BMU (mineral and mass is lost). The amounts resorbed and formed depend on cell number, work, and life span. The authors report that the age-related decrease in bone formation may be the result of a decreased osteoblast number, not function, because life span was reduced, with a decrease in proliferative capacity of osteoprogenitor cells.

◆ Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD Jr. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003 Dec 25;349(26):2483–94.

A striking feature of multiple myeloma, compared with other skeletal malignancies, is the purely lytic nature of the bone lesions. In this study, high expression levels of the wnt antagonist dickkopf 1 (DKK1) were found in myeloma cells. Myeloma supernatants inhibited the differentiation of osteoblasts in culture, and this effect could be partially blocked by antibodies to DKK1. Interruption of osteoblast development by secretion of DKK1 is a potential mechanism for the antiosteogenic effect of multiple myeloma. —GJS

◆ Visser M, Deeg DJ, Lips P; Longitudinal Aging Study Amsterdam. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab. 2003 Dec;88(12):5766–72.

In elderly participants in the Longitudinal Aging Study Amsterdam, a low serum level of 25-hydroxyvitamin D was correlated both with reduced muscle mass by DXA and reduced grip strength. A high parathyroid hormone level was also correlated with reductions in muscle mass and grip strength. The results were not explained by physical activity level, renal function, or body mass index. Better intervention studies will be required to establish a causal relationship between vitamin D insufficiency and muscle loss in the elderly. —GJS

Physiology and metabolism

◆ Hoenderop JG, van Leeuwen JP, van der Eerden BC, Kersten FF, van der Kemp AW, Merillat AM, Waarsing JH, Rossier BC, Vallon V, Hummler E, Bindels RJ. Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5. J Clin Invest. 2003 Dec;112(12):1906–14.

TRPV5 and TRPV6 are calcium channels expressed in kidney and intestine. TRPV6 is a target of vitamin D and the putative primary locus of the effect of vitamin D on intestinal calcium transport. Knockout of TRPV5 reduces calcium reabsorption in the early distal nephron, causing marked hypercalciuria and compensatory hyperabsorption of calcium that is mediated by high 1,25(OH)2D levels. Osteoporosis is present; does it result from cell-autonomous effects of TRPV5 deficiency in bone or chronic high levels? Strangely, the level of parathyroid hormone in serum is unaffected by knockout of TRPV5. —GJS

◆ Jiang D, Franceschi RT, Boules H, Xiao G. Parathyroid Hormone Induction of the Osteocalcin Gene: Requirement for an Osteoblast-Specific Element 1 Sequence in the Promoter and Involvement of Multiple Signaling Pathways. J Biol Chem.2004 Feb 13;279(7):5329–37.

Recommended.

Treatment and drug effects

◆ Bellido T, Ali AA, Plotkin LI, Fu Q, Gubrij I, Roberson PK, Weinstein RS, O'Brien CA, Manolagas SC, Jilka RL. Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. J Biol Chem. 2003 Dec 12;278(50):50259–72.

The anabolic effects of parathyroid hormone (PTH) administration are greatly enhanced by intermittent administration. This paper suggests that antiapoptotic effects of PTH in osteoblasts are self limited. The antiapoptotic effect of PTH is cAMP-dependent and requires both the antiapoptotic protein Bcl2 and Runx2. PTH increases proteasome-mediated degradation of Runx2, and abrogating this process or overexpressing Runx2 increases the duration of the antiapoptotic effect. It will now be important to confirm the implications of these results by PTH treatment of mice with genetic alterations in these pathways. —GJS

◆ Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, Kurihara T, Rogi T, Tanaka S, Suda M, Tamura N, Ogawa Y, Nakao K. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med. 2004 Jan;10(1):80–6.

Achondroplasia results from constitutive activation of fibroblast growth factor receptor 3, which has negative effects on both proliferation and matrix synthesis by chondrocytes. C-type natriuretic peptide (CNP) was previously shown to regulate cartilage growth. Overexpression of CNP in cartilage rescues the achondroplastic phenotype by increasing matrix synthesis, even though chondrocyte proliferation is still abnormal. CNP inhibits MAPK activation, and other MAPK inhibitors also increase matrix synthesis by achondroplastic chondrocytes. CNP is potentially a systemic treatment for achrondroplasia. —GJS

Reviews, commentaries, and perspectives

◆ Cohen MM Jr. The hedgehog signaling network. Am J Med Genet. 2003 Nov 15;123A(1):5–28.

Recommended.

◆ van der Eerden BC, Karperien M, Wit JM. Systemic and local regulation of the growth plate. Endocr Rev. 2003 Dec;24(6):782–801.